Pyridyl inhibitors of hedgehog signalling

ABSTRACT

The invention provides novel inhibitors of hedgehog signaling that are useful as a therapeutic agents for treating malignancies where the compounds have the general formula I: 
     
       
         
         
             
             
         
       
     
     wherein A, X, Y R 1 , R 2 , R 3 , R 4 , m and n are as described herein.

This application claims priority to provisional patent application60/607,367 filed on 2 Sep. 2004.

FIELD OF THE INVENTION

The present invention relates to organic compounds useful for therapyand/or prophylaxis in a mammal, in particular to pyridyl compounds thatinhibit the hedgehog signaling pathway and are useful in the treatmentof hyperproliferative diseases and angiogenesis mediated diseases.

BACKGROUND OF THE INVENTION

Hedgehog (Hh) protein was first identified in Drosophila melanogaster asa segment-polarity gene involved in embryo patterning (Nusslein-Volhardet al., Roux. Arch. Dev. Biol. 193: 267-282 (1984)). Three orthologs ofDrosophila hedgehog (Sonic, Desert and Indian) were later identified tooccur in all vertebrates including fish, birds and mammals. Deserthedgehog (DHh) is expressed principally in the testes, both in mouseembryonic development and in the adult rodent and human; Indian hedgehog(IHh) is involved in bone development during embryogenesis and in boneformation in the adult; and, Sonic hedgehog (SHh) is expressed at highlevels in the notochord and floor plate of developing vertebrateembryos. In vitro explant assays as well as ectopic expression of SHh intransgenic animals have shown that SHh plays a key role in neuronal tubepatterning (Echelard et al., supra.; Ericson et al., Cell 81: 747-56(1995); Marti et al., Nature 375: 322-5 (1995); Krauss et al., Cell 75,1432-44 (1993); Riddle et al., Cell 75: 1401-16 (1993); Roelink et al,Cell 81:445-55 (1995); Hynes et al., Neuron 19: 15-26 (1997)). Hh alsoplays a role in the development of limbs (Krauss et al., Cell 75:1431-44 (1993); Laufer et al., Cell 79, 993-1003 (1994)), somites (Fanand Tessier-Lavigne, Cell 79, 1175-86 (1994); Johnson et al., Cell 79:1165-73 (1994)), lungs (Bellusci et al., Develop. 124: 53-63 (1997) andskin (Oro et al., Science 276: 817-21 (1997)). Likewise, IHh and DHh areinvolved in bone, gut and germinal cell development (Apelqvist et al.,Curr. Biol. 7: 801-4 (1997); Bellusci et al., Dev. Suppl. 124: 53-63(1997); Bitgood et al., Curr. Biol. 6: 298-304 (1996); Roberts et al.,Development 121: 3163-74 (1995)).

Human SHh is synthesized as a 45 kDa precursor protein that uponautocatalytic cleavage yields a 20 kDa N-terminal fragment that isresponsible for normal hedgehog signaling activity; and a 25 kDaC-terminal fragment that is responsible for autoprocessing activity inwhich the N-terminal fragment is conjugated to a cholesterol moiety(Lee, J. J., et al. (1994) Science 266, 1528-1536; Bumcrot, D. A., etal. (1995), Mol. Cell Biol. 15, 2294-2303; Porter, J. A., et al. (1995)Nature 374, 363-366). The N-terminal fragment consists of amino acidresidues 24-197 of the full-length precursor sequence which remainsmembrane-associated through the cholesterol at its C-terminus (Porter,J. A., et al. (1996) Science 274, 255-258; Porter, J. A., et al. (1995)Cell 86, 21-34). Cholesterol conjugation is responsible for the tissuelocalization of the hedgehog signal.

At the cell surface, the Hh signal is thought to be relayed by the 12transmembrane domain protein Patched (Ptc) (Hooper and Scott, Cell 59:751-65 (1989); Nakano et al., Nature 341: 508-13 (1989)) and theG-protein-coupled-like receptor Smoothened (Smo) (Alcedo et al., Cell86: 221-232 (1996); van den Heuvel and Ingham, Nature 382: 547-551(1996)). Both genetic and biochemical evidence support a receptor modelwhere Ptc and Smo are part of a multicomponent receptor complex (Chenand Struhl, Cell 87: 553-63 (1996); Marigo et al., Nature 384: 176-9(1996); Stone et al., Nature 384: 129-34 (1996)). Upon binding of Hh toPtc, the normal inhibitory effect of Ptc on Smo is relieved, allowingSmo to transduce the Hh signal across the plasma membrane. However, theexact mechanism by which Ptc controls Smo activity still has yet to beclarified.

The signaling cascade initiated by Smo results in activation of Glitranscription factors that translocate into the nucleus where theycontrol transcription of target genes. Gli has been shown to influencetranscription of Hh pathway inhibitors such as Ptc and Hip1 in anegative feedback loop indicating that tight control the Hh pathwayactivity is required for proper cellular differentiation and organformation. Uncontrolled activation of Hh signaling pathway areassociated with malignancies in particular those of the brain, skin andmuscle as well as angiogenesis. An explanation for this is that Hhpathway has been shown to regulate cell proliferation in adults byactivation of genes involved in cell cycle progression such as cyclin Dwhich is involved in G1-S transition. Also, SHh blocks cell-cycle arrestmediated by p21, an inhibitor of cyclin dependent kinases. Hh signalingis further implicated in cancer by inducing components in the EGFRpathway (EGF, Her2) involved in proliferation as well as components inthe PDGF (PDGFα) and VEGF pathways involved in angiogenesis. Loss offunction mutations in the Ptc gene have been identified in patients withthe basal cell nevus syndrome (BCNS), a hereditary disease characterizedby multiple basal cell carcinomas (BCCs). Dysfunctional Ptc genemutations have also been associated with a large percentage of sporadicbasal cell carcinoma tumors (Chidambaram et al., Cancer Research 56:4599-601 (1996); Gailani et al., Nature Genet. 14: 78-81 (1996); Hahn etal., Cell 85: 841-51 (1996); Johnson et al., Science 272: 1668-71(1996); Unden et al., Cancer Res. 56: 4562-5; Wicking et al., Am. J.Hum. Genet. 60: 21-6 (1997)). Loss of Ptc function is thought to causean uncontrolled Smo signaling in basal cell carcinoma. Similarly,activating Smo mutations have been identified in sporadic BCC tumors(Xie et al., Nature 391: 90-2 (1998)), emphasizing the role of Smo asthe signaling subunit in the receptor complex for SHh.

Various inhibitors of hedgehog signaling have been investigated such asCyclopamine, a natural alkaloid that has been shown to arrest cell cycleat G0-G1 and to induce apoptosis in SCLC. Cyclopamine is believed toinhibit Smo by binding to its heptahelical bundle. Forskolin has beenshown to inhibit the Hh pathway downstream from Smo by activatingprotein kinase A (PKA) which maintains Gli transcription factorsinactive. Despite advances with these and other compounds, there remainsa need for potent inhibitors of the hedgehog signaling pathway.

SUMMARY OF THE INVENTION

In one aspect of the present invention there is provided novel hedgehoginhibitors having the general formula (I)

wherein

-   A is a carbocycle or heterocycle;-   X is alkylene, NR₄C(O), NR₄C(S), N(C(O)R₁)C(O), NR₄SO, NR₄SO₂,    NR₄C(O)NH, NR₄C(S)NH, C(O)NR₄, C(S)NR₄, NR₄PO or NR₄PO(OH);-   Y is absent, CHR₄, O, S, SO, SO₂ or NR₄;-   R₁ is selected from the group consisting of alkyl, a carbocycle or a    heterocycle each of which is optionally substituted with hydroxyl,    halogen, amino, carbonyl, nitro, cyano, acyl, alkyl, haloalkyl,    alkylsulfonyl, alkylsulfinyl, alkoxy, alkylcarbamoyl, alkanoylamine,    alkylsulfamoyl, alkylsulfonamide, a carbocycle or a heterocycle;    wherein said amino, alkyl, acyl, alkylsulfonyl, alkylsulfinyl,    alkoxy, alkylcarbamoyl, alkanoylamine, alkylsulfamoyl,    alkylsulfonamide, carbocycle and heterocycle substituent is    optionally substituted with amino, halogen, hydroxyl, carbonyl, or a    carbocycle or heterocycle that is optionally substituted with    hydroxyl, amino, halogen, haloalkyl, alkyl, alkoxy or acyl;-   R₂ is halogen, hydroxyl, alkyl, acyl or alkoxy each optionally    substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl,    alkylsulfonyl or alkoxy;-   R₃ is halogen, hydroxyl, carboxyl, alkyl, acyl, alkoxy,    alkoxycarbonyl, carbamoyl, alkylsulfide, alkylsulfinyl,    alkylsulfonyl, a carbocycle or a heterocycle wherein each alkyl,    acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide,    alkylsulfinyl, alkylsulfonyl, carbocycle and heterocycle is    optionally substituted with hydroxyl, halogen, amino, nitro, alkyl,    acyl, alkylsulfonyl or alkoxy;-   R₄ is H or alkyl;-   m is 0-3;-   n is 0-3;-   and salts and solvates thereof.

In another aspect of the invention, there are provided compositionscomprising compounds of formula I and a carrier, diluent or excipient.

In another aspect of the invention, there is provided a method fortreating cancer comprising administering an effective amount of acompound of formula I to a mammal in need thereof.

In another aspect of the invention, there is provided a method forinhibiting hedgehog signaling in a cell comprising contacting said cellwith a compound of formula I.

In another aspect of the invention, there is provided a method fortreating a disease or condition associated with the hedgehog signalingin a mammal, comprising administering to said mammal an effective amountof a compound of formula I.

In another aspect of the invention, there are provided processes forpreparing compounds of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

“Acyl” means a carbonyl containing substituent represented by theformula —C(O)—R in which R is H, alkyl, a carbocycle, a heterocycle,carbocycle-substituted alkyl or heterocycle-substituted alkyl whereinthe alkyl, alkoxy, carbocycle and heterocycle are as defined herein.Acyl groups include alkanoyl (e.g. acetyl), aroyl (e.g. benzoyl), andheteroaroyl.

“Alkyl” means a branched or unbranched, saturated or unsaturated (i.e.alkenyl, alkynyl) aliphatic hydrocarbon group, having up to 12 carbonatoms unless otherwise specified. When used as part of another term, forexample “alkylamino”, the alkyl portion is preferably a saturatedhydrocarbon chain, however also includes unsaturated hydrocarbon carbonchains such as “alkenylamino” and “alkynylamino. “Alkylphosphinate”means a —P(O)R-alkyl group wherein R is H, alkyl, carbocycle-alkyl orheterocycle-alkyl. Examples of preferred alkyl groups include methyl,ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl,2,2-dimethylbutyl, n-heptyl, 3-heptyl, 2-methylhexyl, and the like. Theterms “lower alkyl” “C₁-C₄ alkyl” and “alkyl of 1 to 4 carbon atoms” aresynonymous and used interchangeably to mean methyl, ethyl, 1-propyl,isopropyl, cyclopropyl, 1-butyl, sec-butyl or t-butyl. Unless specified,substituted, alkyl groups may contain one (preferably), two, three orfour substituents which may be the same or different. Examples of theabove substituted alkyl groups include, but are not limited to;cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl,propionyloxymethyl, aminomethyl, carboxymethyl, carboxyethyl,carboxypropyl, alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl,carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl,acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl,6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(iso-propyl),2-carbamoyloxyethyl and the like. The alkyl group may also besubstituted with a carbocycle group. Examples include cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl groups, aswell as the corresponding -ethyl, -propyl, -butyl, -pentyl, -hexylgroups, etc. Preferred substituted alkyls are substituted methyls e.g. amethyl group substituted by the same substituents as the “substitutedC_(n)-C_(m) alkyl” group. Examples of the substituted methyl groupinclude groups such as hydroxymethyl, protected hydroxymethyl (e.g.tetrahydropyranyloxymethyl), acetoxymethyl, carbamoyloxymethyl,trifluoromethyl, chloromethyl, carboxymethyl, bromomethyl andiodomethyl.

“Amidine” or “amidino” means the group —C(NH)—NRR wherein each R isindependently H, OH, alkyl, alkoxy, a carbocycle, a heterocycle, acarbocycle-substituted alkyl or a heterocycle-substituted alkyl; or bothR groups together form a heterocycle. A preferred amidine is the group—C(NH)—NH₂.

“Amino” denotes primary (i.e. —NH₂), secondary (i.e. —NRH) and tertiary(i.e. —NRR) amines wherein R is independently alkyl, a carbocycle (e.g.aryl), a heterocycle (e.g. heteroaryl), carbocycle-substituted alkyl(e.g. benzyl) or a heterocycle-substituted alkyl or alternatively two Rgroups together with the nitrogen atom from which they depend form aheterocycle. Particular secondary and tertiary amines are alkylamine,dialkylamine, arylamine, diarylamine, aralkylamine and diaralkylamine.Particular secondary and tertiary amines are methylamine, ethylamine,propylamine, isopropylamine, phenylamine, benzylamine dimethylamine,diethylamine, dipropylamine and diisopropylamine.

“Amino-protecting group” as used herein refers to a derivative of thegroups commonly employed to block or protect an amino group whilereactions are carried out on other functional groups on the compound.Examples of such protecting groups include carbamates, amides, alkyl andaryl groups, imines, as well as many N-heteroatom derivatives which canbe removed to regenerate the desired amine group. Preferred aminoprotecting groups are Boc, Fmoc and Cbz. Further examples of thesegroups are found in T. W. Greene and P. G. M. Wuts, “Protective Groupsin Organic Synthesis”, 2^(nd) ed., John Wiley & Sons, Inc., New York,N.Y., 1991, chapter 7; E. Haslam, “Protective Groups in OrganicChemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973,Chapter 5, and T. W. Greene, “Protective Groups in Organic Synthesis”,John Wiley and Sons, New York, N.Y., 1981. The term “protected amino”refers to an amino group substituted with one of the aboveamino-protecting groups.

“Aryl” when used alone or as part of another term means a carbocyclicaromatic group whether or not fused having the number of carbon atomsdesignated or if no number is designated, up to 14 carbon atoms. Arylgroups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl,and the like (see e.g. Lang's Handbook of Chemistry (Dean, J. A., ed)13^(th) ed. Table 7-2 [1985]). In a particular embodiment aryl may bephenyl. Substituted phenyl or substituted aryl denotes a phenyl group oraryl group substituted with one, two, three, four or five, such as 1-2,1-3 or 1-4 substituents chosen, unless otherwise specified, from halogen(F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (forexample C₁-C₆ alkyl), alkoxy (for example C₁-C₆ alkoxy), benzyloxy,carboxy, protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, aminomethyl, protectedaminomethyl, trifluoromethyl, alkylsulfonylamino, arylsulfonylamino,heterocyclylsulfonylamino, heterocyclyl, aryl, or other groupsspecified. One or more methyne (CH) and/or methylene (CH₂) groups inthese substituents may in turn be substituted with a similar group asthose denoted above. Examples of the term “substituted phenyl” includesbut is not limited to a mono- or di(halo)phenyl group such as2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl,4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl,2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, theprotected-hydroxy derivatives thereof and the like; a nitrophenyl groupsuch as 3- or 4-nitrophenyl; a cyanophenyl group, for example,4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl,4-(iso-propyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; amono or di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl,3-methoxy-4-benzyloxyphenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl,4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl andthe like; 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or(protected carboxy)phenyl group such 4-carboxyphenyl; a mono- ordi(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; amono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono-or di(N-(methylsulfonylamino))phenyl such as3-(N-methylsulfonylamino))phenyl. Also, the term “substituted phenyl”represents disubstituted phenyl groups where the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl,2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenylgroups where the substituents are different, for example3-methoxy-4-benzyloxy-6-methyl sulfonylamino,3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstitutedphenyl groups where the substituents are different such as3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino. Substitutedphenyl groups include 2-chlorophenyl, 2-aminophenyl, 2-bromophenyl,3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl, 4-methoxyphenyl,3-ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl,3-methoxy-4-benzyloxyphenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-6-methyl sulfonyl aminophenylgroups. Fused aryl rings may also be substituted with any (for example1, 2 or 3) of the substituents specified herein in the same manner assubstituted alkyl groups.

“Carbamoyl” means an aminocarbonyl containing substituent represented bythe formula —C(O)N(R)₂ in which R is H, hydroxyl, alkoxy, alkyl, acarbocycle, a heterocycle, carbocycle-substituted alkyl or alkoxy, orheterocycle-substituted alkyl or alkoxy wherein the alkyl, alkoxy,carbocycle and heterocycle are as herein defined. Carbamoyl groupsinclude alkylaminoecarbonyl (e.g. ethylaminocarbonyl, Et-NH—CO—),arylaminocarbonyl (e.g. phenylaminocarbonyl), aralkylaminocarbonyl (e.g.benzoylaminocarbonyl) a heterocycleaminocarbonyl (e.g.piperizinylaminocarbonyl), and in particular a heteroarylaminocarbonyl(e.g. pyridylaminocarbonyl).

“Carbocyclyl”, “carbocyclic”, “carbocycle” and “carbocyclo” alone andwhen used as a moiety in a complex group such as a carbocycloalkylgroup, refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to14 carbon atoms and preferably 3 to 7 carbon atoms which may besaturated or unsaturated, aromatic or non-aromatic. Preferred saturatedcarbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl groups and more preferred are cyclopropyl and cyclohexyl andmost preferred is cyclohexyl. Preferred unsaturated carbocycles arearomatic e.g. aryl groups as previously defined, the most preferredbeing phenyl. The terms “substituted carbocyclyl”, “substitutedcarbocycle” and “substituted carbocyclo” unless otherwise specified meanthese groups substituted by the same substituents as the “substitutedalkyl” group.

“Carboxy-protecting group” as used herein refers to one of the esterderivatives of the carboxylic acid group commonly employed to block orprotect the carboxylic acid group while reactions are carried out onother functional groups on the compound. Examples of such carboxylicacid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl,3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl,2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl,benzhydryl, 4,4′-dimethoxybenzhydryl, 2,2′,4,4′-tetramethoxybenzhydryl,alkyl such as t-butyl or t-amyl, trityl, 4-methoxytrityl,4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, 2-phenylprop-2-yl,trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl,beta-(trimethylsilyl)ethyl, beta-(di(n-butyl)methylsilyl)ethyl,p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The speciesof carboxy-protecting group employed is not critical so long as thederivatized carboxylic acid is stable to the condition of subsequentreaction(s) on other positions of the molecule and can be removed at theappropriate point without disrupting the remainder of the molecule. Inparticular, it is important not to subject a carboxy-protected moleculeto strong nucleophilic bases, such as lithium hydroxide or NaOH, orreductive conditions employing highly activated metal hydrides such asLiAlH₄. (Such harsh removal conditions are also to be avoided whenremoving amino-protecting groups and hydroxy-protecting groups,discussed below.) Preferred carboxylic acid protecting groups are thealkyl (e.g. methyl, ethyl, t-butyl), allyl, benzyl and p-nitrobenzylgroups. Similar carboxy-protecting groups used in the cephalosporin,penicillin and peptide arts can also be used to protect a carboxy groupsubstituents. Further examples of these groups are found in T. W. Greeneand P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 2^(nd) ed.,John Wiley & Sons, Inc., New York, N.Y., 1991, chapter 5; E. Haslam,“Protective Groups in Organic Chemistry”, J. G. W. McOmie, Ed., PlenumPress, New York, N.Y., 1973, Chapter 5, and T. W. Greene, “ProtectiveGroups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981,Chapter 5. The term “protected carboxy” refers to a carboxy groupsubstituted with one of the above carboxy-protecting groups.

“Guanidine” means the group —NH—C(NH)—NHR wherein R is H, alkyl, acarbocycle, a heterocycle, a carbocycle-substituted alkyl, or aheterocycle-substituted alkyl. A particular guanidine group is—NH—C(NH)—NH₂.

“Heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or“heterocyclo” alone and when used as a moiety in a complex group such asa heterocycloalkyl group, are used interchangeably and refer to anymono-, bi-, or tricyclic, saturated or unsaturated, aromatic(heteroaryl) or non-aromatic ring having the number of atoms designated,generally from 5 to about 14 ring atoms, where the ring atoms are carbonand at least one heteroatom (nitrogen, sulfur or oxygen) and preferably1 to 4 heteroatoms. “Heterocyclosulfonyl” means a —SO₂-heterocyclegroup; “heterocyclosulfinyl” means a —SO-heterocycle group. Typically, a5-membered ring has 0 to 2 double bonds and 6- or 7-membered ring has 0to 3 double bonds and the nitrogen or sulfur heteroatoms may optionallybe oxidized (e.g. SO, SO₂), and any nitrogen heteroatom may optionallybe quaternized. Preferred non-aromatic heterocycles include morpholinyl(morpholino), pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl,2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl,tetrahydrothietanyl, aziridinyl, azetidinyl, 1-methyl-2-pyrrolyl,piperazinyl and piperidinyl. A “heterocycloalkyl” group is a heterocyclegroup as defined above covalently bonded to an alkyl group as definedabove. Preferred 5-membered heterocycles containing a sulfur or oxygenatom and one to three nitrogen atoms include thiazolyl, in particularthiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, preferablyoxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and1,2,4-oxadiazol-5-yl. Preferred 5-membered ring heterocycles containing2 to 4 nitrogen atoms include imidazolyl, preferably imidazol-2-yl;triazolyl, preferably 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl,1,2,4-triazol-5-yl, and tetrazolyl, preferably 1H-tetrazol-5-yl.Preferred benzo-fused 5-membered heterocycles are benzoxazol-2-yl,benzthiazol-2-yl and benzimidazol-2-yl. Preferred 6-memberedheterocycles contain one to three nitrogen atoms and optionally a sulfuror oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, andpyrid-4-yl; pyrimidyl, preferably pyrimid-2-yl and pyrimid-4-yl;triazinyl, preferably 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl;pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridineN-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl,pyrimid-4-yl, pyridazinyl and the 1,3,4-triazin-2-yl groups, are apreferred group. Substituents for optionally substituted heterocycles,and further examples of the 5- and 6-membered ring systems discussedabove can be found in W. Druckheimer et al., U.S. Pat. No. 4,278,793.

“Heteroaryl” alone and when used as a moiety in a complex group such asa heteroaralkyl group, refers to any mono-, bi-, or tricyclic aromaticring system having the number of atoms designated where at least onering is a 5-, 6- or 7-membered ring containing from one to fourheteroatoms selected from the group nitrogen, oxygen, and sulfur, andpreferably at least one heteroatom is nitrogen (Lang's Handbook ofChemistry, supra). Included in the definition are any bicyclic groupswhere any of the above heteroaryl rings are fused to a benzene ring.Heteroaryls in which nitrogen or oxygen is the heteroatom are preferred.The following ring systems are examples of the heteroaryl (whethersubstituted or unsubstituted) groups denoted by the term “heteroaryl”:thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl,thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl,dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl,dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl,tetrazolo[1,5-b]pyridazinyl and purinyl, as well as benzo-fusedderivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl,benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl. Aparticularly preferred group of “heteroaryl” include; 1,3-thiazol-2-yl,4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt,1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl,1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl,2-hydroxy-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-ylsodium salt, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl,1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl,2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl,1,3,4-thiadiazol-5-yl, 2-thiol-1,3,4-thiadiazol-5-yl,2-(methylthio)-1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl,1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl,1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl,1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-ylsodium salt, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonicacid)-1H-tetrazol-5-yl sodium salt, 2-methyl-1H-tetrazol-5-yl,1,2,3-triazol-5-yl, 1-methyl-1,2,3-triazol-5-yl,2-methyl-1,2,3-triazol-5-yl, 4-methyl-1,2,3-triazol-5-yl, pyrid-2-ylN-oxide, 6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl,1-methylpyrid-2-yl, 1-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl,1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-astriazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl sodium salt,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-astriazin-3-yl sodium salt,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-as-triazin-3-yl,2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl,tetrazolo[1,5-b]pyridazin-6-yl and8-aminotetrazolo[1,5-b]-pyridazin-6-yl. An alternative group of“heteroaryl” includes; 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt,1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 1H-tetrazol-5-yl,1-methyl-1H-tetrazol-5-yl,1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl,1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-ylsodium salt, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonicacid)-1H-tetrazol-5-yl sodium salt, 1,2,3-triazol-5-yl,1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,1,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,tetrazolo[1,5-b]pyridazin-6-yl, and8-aminotetrazolo[1,5-b]pyridazin-6-yl.

“Hydroxy-protecting group” as used herein refers to a derivative of thehydroxy group commonly employed to block or protect the hydroxy groupwhile reactions are carried out on other functional groups on thecompound. Examples of such protecting groups includetetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, andsilylethers (e.g. TBS, TBDPS) groups. Further examples of these groupsare found in T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, 2^(nd) ed., John Wiley & Sons, Inc., New York, N.Y.,1991, chapters 2-3; E. Haslam, “Protective Groups in Organic Chemistry”,J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, andT. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley andSons, New York, N.Y., 1981. The term “protected hydroxy” refers to ahydroxy group substituted with one of the above hydroxy-protectinggroups.

“Pharmaceutically acceptable salts” include both acid and base additionsalts. “Pharmaceutically acceptable acid addition salt” refers to thosesalts which retain the biological effectiveness and properties of thefree bases and which are not biologically or otherwise undesirable,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like,and organic acids may be selected from aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids such as formic acid, acetic acid, propionic acid, glycolicacid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid,citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilicacid, benzoic acid, cinnamic acid, mandelic acid, embonic acid,phenylacetic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly preferred are the ammonium, potassium, sodium,calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases includes salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, TEA, tripropylamine,ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, methylglucamine, theobromine,purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins andthe like. Particularly preferred organic non-toxic bases areisopropylamine, diethylamine, ethanolamine, trimethamine,dicyclohexylamine, choline, and caffeine.

“Phosphinate” means —P(O)R—OR wherein each R is independently H, alkyl,carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl. Particularphosphinate groups are alkylphosphinate (i.e. —P(O)R—O-alkyl), forexample —P(O)Me-OEt.

“Sulfamoyl” means —SO₂—N(R)₂ wherein each R is independently H, alkyl,carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl. Particularsulfamoyl groups are alkylsulfamoyl, for example methylsulfamoyl(—SO₂—NHMe); arylsulfamoyl, for example phenylsulfamoyl;aralkylsulfamoyl, for example benzylsulfamoyl.

“Sulfinyl” means a —SO—R group wherein R is alkyl, carbocycle,heterocycle, carbocycloalkyl or heterocycloalkyl. Particular sulfinylgroups are alkylsulfinyl (i.e. —SO-alkyl), for example methylsulfinyl;arylsulfinyl (i.e. —SO-aryl) for example phenylsulfinyl;aralkylsulfinyl, for example benzylsulfinyl.

“Sulfonamide” means —NR—SO₂—R wherein each R is independently H, alkyl,carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl), acarbocycle or a heterocycle. Particular sulfonamide groups arealkylsulfonamide (e.g. —NH—SO₂-alkyl), for example methylsulfonamide;arylsulfonamdie (i.e. —NH—SO₂-aryl) for example phenylsulfonamide;aralkylsulfonamide, for example benzylsulfonamide.

“Sulfonyl” means a —SO₂—R group wherein R is alkyl, carbocycle,heterocycle, carbocycloalkyl or heterocycloalkyl. Particular sulfonylgroups are alkylsulfonyl (i.e. —SO₂-alkyl), for example methylsulfonyl;arylsulfonyl, for example phenylsulfonyl; aralkylsulfonyl, for examplebenzylsulfonyl.

The phrase “and salts and solvates thereof” as used herein means thatcompounds of the inventions may exist in one or a mixture of salts andsolvate forms. For example a compound of the invention may besubstantially pure in one particular salt or solvate form or else may bemixtures of two or more salt or solvate forms.

The present invention provides novel compounds having the generalformula I:

wherein A, X, Y, R₁, R₂, and R₃ are as defined herein.

A is a carbocycle or heterocycle ring substituted with 0 to 3 (e.g. n is0-3) R₂ groups selected from the group consisting of halogen, hydroxyl,alkyl, acyl or alkoxy each optionally substituted with hydroxyl,halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy. In aparticular embodiment, A is optionally substituted aryl or heteroaryl.In particular embodiment A is optionally substituted benzene, thiophene,thiazole, imidazole, pyrrole, N-alkyl pyrrole, pyridine, pyrazole orN-alkyl pyrazole. In a particular embodiment A is a ring selected fromthe group consisting of A¹, A², A³, A⁴ A⁵, A⁶ and A⁷:

wherein Z₁ is O, S or NR₅ wherein R₅ is H or alkyl; Z₂ is CH, CR_(2′) orN; R₂ is halogen, hydroxyl, alkyl, acyl or alkoxy each optionallysubstituted with hydroxyl, halogen, amino, nitro, alkyl, acyl,alkylsulfonyl or alkoxy; R_(2′) is H, halogen, hydroxyl, alkyl, acyl oralkoxy each optionally substituted with hydroxyl, halogen, amino, nitro,alkyl, acyl, alkylsulfonyl or alkoxy; and n is 0-3. In a particularembodiment A is the ring of formula A¹. In a particular embodiment, A isthe ring of formula A¹ wherein Z₁ is S and Z₂ is CH or N. In anotherembodiment, A is the ring of formula A¹ wherein Z₁ is S and Z₂ is CH,i.e. thiophene. In another embodiment, A is the ring of formula A¹wherein Z₁ is S and Z₂ is N, i.e. thiazole. In another embodiment, A isthe ring of formula A¹ wherein R_(2′) is H. In embodiment, A is the ringof formula A¹ wherein R_(2′) is methyl. In another embodiment, A is thering A¹ wherein R_(2′) is methyl. In a particular embodiment A is ringA². In another embodiment, A is the ring of formula A¹ wherein R₂ may beabsent, i.e. n is 0. In another embodiment, n is 1 and R₂ is Cl. Inanother particular embodiment A is the ring of formula A³. In anembodiment, A is a ring of formula A³ wherein Z, is S and Z₂ is N, i.e.a thiazole. In another embodiment, A is a ring of formula A³ wherein Z,is S, Z₂ is N and R₂′ is Cl. In another embodiment, A is a ring offormula A³ wherein Z₁ is S, Z₂ is CH (i.e. thiophene) and R₂′ is Cl.

In a particular embodiment A is the ring A^(1a), A^(1b), A^(2a), A^(3a),A^(3b), A^(4a), A^(5a), A^(6a), A^(7a):

In a particular embodiment A is the ring of formula A^(1a). In anotherembodiment A is the ring of formula A^(1b). In another embodiment A isthe ring of formula A^(2a). In another embodiment A is the ring offormula A^(3a). In another embodiment A is the ring of formula A^(3b).In another embodiment A is the ring of formula A^(4a).

X is alkylene, NR₄C(O), NR₄C(S), N(C(O)R₁)C(O), NR₄SO, NR₄SO₂,NR₄C(O)NH, NR₄C(S)NH, C(O)NR₄, C(S)NR₄, NR₄PO or NR₄PO(OH) wherein R₄ isH or alkyl. In a particular embodiment X is NR₄C(O) which forms an amidelinkage between ring A and R₁. In another embodiment, X is N₄C(S), whichforms a thioamide linkage between ring A and R₁. In another embodiment,X is NR₄C(O)NH which forms a urea linkage between ring A and R₁. Inanother embodiment X is NR₄C(S)NH which with NR₂ forms a thiourealinkage between ring A and R₁. In another embodiment X is N(C(O)R₁)C(O)i.e. a nitrogen with two —C(O)R₁ groups pending therefrom.

Y is absent, CHR₄, O, S, SO, SO₂ or NR₄ wherein R₄ is as defined herein.In a particular embodiment Y is CHR₄. In a particular embodiment Y isNR₄. In a particular embodiment Y is O. In a particular embodiment Y isS. In a particular embodiment Y is SO. In a particular embodiment Y isSO₂. In another embodiment Y is absent i.e. ring A is directly attachedto the pyridyl ring at the 2-position.

R₁ is selected from the group consisting of alkyl, a carbocycle or aheterocycle each of which is optionally substituted with hydroxyl,halogen, amino, carboxyl, amidino, guanidino, carbonyl (i.e. ═O), nitro,cyano, acyl, alkyl, haloalkyl, sulfonyl, sulfinyl, alkoxy, akylthio,carbamoyl, acylamino, sulfamoyl, sulfonamide, a carbocycle or aheterocycle; wherein said amino, amidino, alkyl, acyl, sulfonyl,sulfinyl, alkoxy, alkylthio, carbamoyl, acylamino, sulfamoyl,sulfonamide, carbocycle and heterocycle substituent is optionallysubstituted with, halogen, haloakyl, hydroxyl, carboxyl, carbonyl, or anamino, alkyl, alkoxy, acyl, sulfonyl, sulfinyl, phosphinate, carbocycleor heterocycle that is optionally substituted with hydroxyl, carboxyl,carbonyl, amino, halogen, haloalkyl, alkyl, alkoxy, alkylthio, sulfonyl,sulfinyl, acyl, a carbocycle or a heterocycle.

In another embodiment R₁ is selected from the group consisting of alkyl,a carbocycle or a heterocycle each of which is optionally substitutedwith hydroxyl, halogen, amino, carbonyl, nitro, cyano, acyl, alkyl,haloalkyl, alkylsulfonyl, alkylsulfinyl, alkoxy, alkylcarbamoyl (i.e.—CONR— alkyl wherein R is H or alkyl), alkanoylamine (i.e. —NRCO-alkylwherein R is H or alkyl), alkylsulfamoyl (i.e. —SO₂NR—alkyl wherein R isH or alkyl), alkylsulfonamide (i.e. —NR—SO₂-alkyl wherein R is H oralkyl), a carbocycle or a heterocycle; wherein said amino, alkyl, acyl,alkylsulfonyl, alkylsulfinyl, alkoxy, alkylcarbamoyl, alkanoylamine,alkylsulfamoyl, alkylsulfonamide, carbocycle and heterocycle substituentis optionally substituted with amino, halogen, hydroxyl, carbonyl, or acarbocycle or heterocycle that is optionally substituted with hydroxyl,amino, halogen, haloalkyl, alkyl, alkoxy or acyl.

In a particular embodiment R₁ is an optionally substituted aryl orheteroaryl. In a particular embodiment R₁ is an optionally substitutedphenyl group. In another particular embodiment R₁ is an optionallysubstituted pyridine group. In a particular embodiment R₁ is of formulaIIa, IIb, IIc, IId, IIe, IIf, IIg, IIh, IIi, IIj, IIk, IIl, IIm, IIn orIIo:

wherein W is O, S or NR₇ wherein R₇ is H, alkyl, acyl, a carbocycle or aheterocycle wherein said alkyl, acyl, carbocycle and heterocycle areeach optionally substituted with 1-3 amino, halogen, hydroxyl andhaloalkyl; o is 0-3. In a particular embodiment W is S.

R₆ in each instance is independently hydroxyl, halogen, amino, carboxyl,amidino, guanidino, carbonyl, nitro, cyano, acyl, alkyl, haloalkyl,sulfonyl, sulfinyl, alkoxy, akylthio, carbamoyl, acylamino, sulfamoyl,sulfonamide, a carbocycle or a heterocycle; wherein said amino, amidino,alkyl, acyl, sulfonyl, sulfinyl, alkoxy, alkylthio, carbamoyl,acylamino, sulfamoyl, sulfonamide, carbocycle and heterocyclesubstituent is optionally substituted with, halogen, haloakyl, hydroxyl,carboxyl, carbonyl, or an amino, alkyl, alkoxy, acyl, sulfonyl,sulfinyl, phosphinate, carbocycle or heterocycle that is optionallysubstituted with hydroxyl, carboxyl, carbonyl, amino, halogen,haloalkyl, alkyl, alkoxy, alkylthio, sulfonyl, sulfinyl, acyl, acarbocycle or a heterocycle.

In a particular embodiment R₆ in each instance is independentlyhydroxyl, halogen, amino, carbonyl, nitro, cyano, acyl, alkyl, sulfonyl,alkylsulfonyl, alkylsulfinyl, alkoxy, alkylcarbamoyl, alkanoylamine,alkylsulfamoyl, alkylsulfonamide, a carbocycle or a heterocycle; whereinsaid amino, alkyl, carbonyl, acyl, sulfonyl, alkylsulfonyl,alkylsulfinyl, alkoxy, alkylcarbamoyl, alkanoylamine, alkylsulfamoyl,alkylsulfonamide, carbocycle and heterocycle substituent is optionallysubstituted with amino, halogen, hydroxyl, carbonyl, or a carbocycle orheterocycle that is optionally substituted with hydroxyl, amino,halogen, haloalkyl, alkyl, alkoxy or acyl.

In a particular embodiment R₆ is independently in each instanceoptionally substituted alkyl (e.g. methyl, trifluoromethyl,dimethylaminomethyl, piperidinylmethyl, morpholinomethyl,thiomorpholinomethyl); halogen (e.g. chloro); alkoxy (e.g. methoxy);carbonyl (e.g. morpholinocarbonyl, acetyl); a heterocycle (e.g.morpholino, N-methyl-piperazin-4-yl, N-acetyl-piperazin-4-yl,1H-1,2,4-triazole); alkylamino (e.g. i-butylamino, benzylamino,hydroxyethylamino, methoxyethylamino, dimethylaminoethylamino,morpholinoethylamino, morpholinopropylamino,pyrrolidin-2-one-substituted propylamino, imidazole-ethylamino,imidazole-propylamino); arylamino (e.g. phenylamino); alkylcarbamoyl(e.g. dimethylcarbamoyl, i-butylaminocarbonyl); alkylsulfamoyl (e.g.propylaminosulfonyl, i-butylaminosulfonyl, dimethylaminosulfonyl,dimethylaminoethyl hydroxyethylaminosulfonyl, methoxyethylaminosulfonyl,methoxypropylaminosulfonyl, methylsulfonylethylaminosulfonyl,imidazole-substituted propylaminosulfonyl, hydroxypropylaminosulfonyl,2-hydroxypropylaminosulfonyl); or sulfonyl (e.g. methylsulfonyl,ethylsulfonyl, aminosulfonyl, dimethylaminopropylsulfonyl,N-methyl-piperazin-4-yl-sulfonyl, morpholino-4-yl-sulfonyl,trifluoromethylsulfonyl).

In a particular embodiment R₇ is H. In another particular embodiment R₇is optionally substituted acyl. In another particular embodiment R₇ isoptionally substituted alkyl (e.g. methyl). In another particularembodiment R₇ is optionally substituted acyl (e.g. acetyl, benzoyl). Inanother particular embodiment R₇ is an optionally substituted aryl group(e.g. phenyl, benzyl).

In a particular embodiment R₁ is the group of formula IIa. In suchembodiment R₆ may be alkoxy and o is 1, 2 or 3. Particular Ha groups areIIa¹-IIa²⁸:

In another particular embodiment R₁ is the group of formula IIb. In suchembodiment R₆ may be alkyl or haloalkyl (e.g. CF₃). Particular IIbgroups are IIb¹-IIb³:

In a particular embodiment R₁ is the group of formula IIc. In suchembodiment W may be S and o is 0. In another particular embodiment R₁ isthe group of formula IId. In such embodiment o may be 0. In anotherparticular embodiment R₁ is the group of formula IIe. In such embodimento may be 0. In another particular embodiment R₁ is the group of formulaIIf. In such embodiment o may be 0.

In another particular embodiment R₁ is the group of formula IIn. In suchembodiment o may be 0 or 2 and R₆ may be alkyl or aryl. In a particularembodiment, group IIn has the formula IIn¹:

In another particular embodiment R₁ is the group of formula IIo. In suchembodiment o may be 0 or 2 and R₆ may be alkyl or aryl. In a particularembodiment, group IIo has the formula IIo¹:

R₂ is halogen, hydroxyl, alkyl, acyl or alkoxy each optionallysubstituted with hydroxyl, halogen, amino, nitro, alkyl, acyl,alkylsulfonyl or alkoxy. n is 0-3, for example 0 or 1. In a particularembodiment R₂ is hydroxyl. In a particular embodiment R₂ is alkyl oralkyl substituted with halogen, methyl or trifluoromethyl. In aparticular embodiment R₂ is acyl, for example alkanoyl e.g. acetyl. In aparticular embodiment R₂ is halogen, for example Cl or F. In anotherparticular embodiment R₂ is alkoxy, for example methoxy or ethoxy.

R₃ is halogen, hydroxyl, carboxyl, alkyl, acyl, alkoxy, alkoxycarbonyl,carbamoyl, alkylsulfide, sulfinyl, sulfonyl, a carbocycle or aheterocycle wherein each alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl,alkylsulfide, sulfinyl, sulfonyl, carbocycle and heterocycle isoptionally substituted with hydroxyl, halogen, amino, nitro, alkyl,acyl, sulfonyl or alkoxy. In a particular embodiment R₃ is halogen,hydroxyl, carboxyl, alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl,alkylsulfide, alkylsulfinyl, alkylsulfonyl, a carbocycle or aheterocycle wherein each alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl,alkylsulfide, alkylsulfinyl, alkylsulfonyl, carbocycle and heterocycleis optionally substituted with hydroxyl, halogen, amino, nitro, alkyl,acyl, alkylsulfonyl or alkoxy; while m is 0 to 3. In a particularembodiment, R₃ is halogen (e.g. F), carboxyl, or optionally substitutedalkyl (e.g. methyl, hydroxymethyl, dimethylaminomethyl), alkoxycarbonyl(e.g. methoxycarbonyl) or carbamoyl (e.g. dimethylaminocarbonyl). In aparticular embodiment m is 0, i.e. R₃ is absent. In another particularembodiment m is 1-3.

In a particular embodiment, compounds of the invention are representedby the general formula Ib:

wherein X, R₁, R₃ and m are as defined herein and R₈ is halogen. In anembodiment, compounds of the invention have the general formula Ib and Xis NR₄CO. In further embodiment, compounds are of formula Ib and R₃ is Hor methyl.

In another particular embodiment, compounds of the invention arerepresented by the general formula Ib′:

wherein X, R₃, R₆, m and o are as defined herein; R₈ is a halogen; andring B is a carbocycle or heterocycle. In a particular embodiment R₈ isCl. In a particular embodiment ring B is phenyl or pyridyl. In aparticular embodiment X is NR₄C(O) and R₄ is as defined herein.

In another particular embodiment, compounds of the invention have thegeneral formula Ic:

wherein X, R₁, R₃ and m are as defined herein. In an embodiment,compounds of the invention have the general formula Ib and X is NR₄CO.In a further embodiment, compounds are of formula Ic and R₃ is H ormethyl and m is 0 or 1.

In another particular embodiment, compounds of the invention have thegeneral formula Id:

wherein X, R₁, R₃ and m are as defined herein. In an embodiment,compounds of the invention have the general formula Ib and X is NR₄CO.In a further embodiment, compounds are of formula Id and R₃ is H, Cl ortrifluoromethyl and m is 0 or 1.

Particular compounds of the invention include, but are not limited tothe following:

Compounds of the invention may contain one or more asymmetric carbonatoms. Accordingly, the compounds may exist as diastereomers,enantiomers or mixtures thereof. The syntheses of the compounds mayemploy racemates, diastereomers or enantiomers as starting materials oras intermediates. Diastereomeric compounds may be separated bychromatographic or crystallization methods. Similarly, enantiomericmixtures may be separated using the same techniques or others known inthe art. Each of the asymmetric carbon atoms may be in the R or Sconfiguration and both of these configurations are within the scope ofthe invention.

The invention also encompasses prodrugs of the compounds describedabove. Suitable prodrugs include known amino-protecting andcarboxy-protecting groups which are released, for example hydrolyzed, toyield the parent compound under physiologic conditions. A particularclass of prodrugs are compounds in which a nitrogen atom in an amino,amidino, aminoalkyleneamino, iminoalkyleneamino or guanidino group issubstituted with a hydroxy (OH) group, an alkylcarbonyl (—CO—R) group,an alkoxycarbonyl (—CO—OR), an acyloxyalkyl-alkoxycarbonyl(—CO—O—R—O—CO—R) group where R is a monovalent or divalent group and asdefined above or a group having the formula —C(O)—O—CP1P2-haloalkyl,where P1 and P2 are the same or different and are H, lower alkyl, loweralkoxy, cyano, halo lower alkyl or aryl. Prodrug compounds may beprepared by reacting the compounds of the invention described above withan activated acyl compound to bond a nitrogen atom in the compound ofthe invention to the carbonyl of the activated acyl compound. Suitableactivated carbonyl compounds contain a good leaving group bonded to thecarbonyl carbon and include acyl halides, acyl amines, acyl pyridiniumsalts, acyl alkoxides, in particular acyl phenoxides such asp-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, anddifluorophenoxy acyl. The reactions are generally exothermic and arecarried out in inert solvents at reduced temperatures such as −78 toabout 50° C. The reactions are usually also carried out in the presenceof an inorganic base such as potassium carbonate or sodium bicarbonate,or an organic base such as an amine, including pyridine, TEA, etc. Onemanner of preparing prodrugs is described in U.S. Ser. No. 08/843,369filed Apr. 15, 1997 (corresponding to PCT publication WO9846576) thecontents of which are incorporated herein by reference in theirentirety.

Synthesis

Compounds of the invention are prepared using standard organic synthetictechniques from commercially available starting materials and reagents.It will be appreciated that synthetic procedures employed in thepreparation of compounds of the invention will depend on the particularsubstituents present in a compound and that various protection anddeprotection procedures may be required as is standard in organicsynthesis. Compounds of the invention in which Y is absent may preparedby a Negishi coupling procedure according to the following generalscheme 1:

in which the pyridyl zinc bromide (or alternatively pyridylzincchloride) is reacted with an iodo or bromo substituted ring A to givethe final compound Ia. Alternatively, compounds Ia of the invention maybe prepared using a Suzuki coupling reaction of a borylated ring A toprovide direct linkage between the appropriate pyridyl and ring Aaccording to scheme 2.

A halogen-substituted ring A is reacted with a boron ester such aspinacol diborane in the presence of palladium catalyst such asPdCl₂(dppf) and the resulting boronate ester is heated with a2-halogen-substituted pyridine and a palladium catalyst to give a finalcompound Ia of the invention.

Compounds of the invention in which Y is NR₄ may prepared by palladiumcatalyzed amination of halogen-substituted ring A with the desired2-aminopyridine according to scheme 3.

Compounds of the invention in which X is NR₄CO may be prepared by thegeneral scheme 4 in which amine-substituted ring A is reacted with thedesired acid chloride Cl—C(O)—R₁.

Alternatively, such compounds may be prepared from by EDC catalyzedcoupling of a carboxy-substituted ring A with an amine-substituted R₁group, i.e. R₁—NR₄H. The same scheme may be used to prepare thioamidecompounds of the invention, i.e. X is NR₄C(S), by employing anappropriate thio acid chloride Cl—C(S)—R₁ in the acylation step.

Compounds of the invention in which X is C(O)NR₄ may be similarlyprepared by reacting an amine-substituted ring A with acarboxy-substituted R₁ group and EDC catalyst according to scheme 5.

A similar scheme may be used to prepare thioamide compounds of theinvention, i.e. X is C(S)NR₄, by employing an appropriate thioicacid-substituted ring A (e.g. —C(S)OH) or by converting the amide withLawesson's reagent.

Compounds of the invention in which X is NR₄C(O)NH may be preparedaccording to the general scheme 6 by reacting amine-substituted ring Awith the appropriate isocyanate R₁—NCO.

The same scheme may be used to prepare thiourea compounds of theinvention, i.e. X is NR₄C(S)NH, by employing an appropriateisothiocyanate R₁—NCS in place of the isocyanate R₁—NCO.

Compounds of the invention in which X is NR₄SO₂ may be preparedaccording to the general scheme 7 by reacting an amine-substituted ringA with the appropriate sulfonyl chloride R₁—S(O₂)Cl in the presence of anon-nucleophilic base such as TEA or diisopropylethylamine to form thedesired sulfonamide.

Compounds of the invention in which X is NR₄SO are similarly preparedusing the appropriate sulfinyl chloride R₁—SO—Cl instead of the sulfonylchloride R₁—S(O₂)Cl.

Compounds of the invention having the structure of formula Ib′ in whichX is NHCO (i.e. formula Ib″) may be prepared according to the generalscheme 8 in which R₃, R₆, m and o are as defined herein and Q is Cl, Bror I; Q′ is halogen, OH, OR wherein R is an activating group; L is Br, Ior OTf (e.g. O—SO2-CF₃):

The zinc halide pyridine reagent (a) is reacted with2-chloro-5-nitro-benzene reagent (b) in a Negishi coupling reaction inthe presence of a suitable catalyst such as palladiumtetrakis(triphenylphosphine) complex (Pd(PPh₃)₄). In a particularembodiment, the palladium tetrakis(triphenylphosphine) catalyst isstabilized with triphenylphosphine (PPh₃). In a particular embodiment Qis Br. In a particular embodiment L is I. In a particular embodiment,the coupling reaction is performed from about 50° C. to about 60° C.

The nitrobenzene reagent (b) may be obtained from activating thecorresponding amine (i.e. 2-chloro-5-nitroaniline) in an aqueoussulfuric acid solution with sodium nitrite and displacing with an Lgroup (e.g. with KI, KBr). In a particular embodiment, L is I. In aparticular embodiment the reaction is performed at less than about 15°C.

The resulting intermediate (c) is reduced, for example with Fe, Zn orSnCl₂ in presence of acid to give the amine intermediate (d). In aparticular embodiment, intermediate (c) is reduced with Fe, for example,in the presence of AcOH in EtOH. In a particular embodiment,intermediate (c) is reduced with Zn, for example in the presence of AcOHin EtOH. In a particular embodiment, intermediate (c) is reduced withSnCl₂, for example in the presence of HCl in EtOH. In a particularembodiment the reduction reaction is performed at about 60° C.

Finally, intermediate (d) is reacted with an activated acid (e) to yieldfinal compound Ib″. In a particular embodiment, the activated acid (e)is an acid halide (e.g. Q′ is chloride) or activated ester (e.g. Q′ isO-EDC). In a particular embodiment the final reaction is performed atabout 0° C.

The compounds of the invention inhibit the hedgehog signaling and areuseful for the treatment of cancers associated with aberrant hedgehogsignaling, for example when Patched fails to, or inadequately, repressesSmoothened (Ptc loss-of-function phenotype) and/or when Smoothened isactive regardless of Patched repression (Smo gain-of-functionphenotype). Examples of such cancer types include basal cell carcinoma,neuroectodermal tumors such as medullablastoma, meningioma, hemangioma,glioblastoma, pancreatic adenocarcinoma, squamous lung carcinoma,small-cell lung carcinoma, non-small cell lung carcinoma,chondrosarcoma, breast carcinoma, rhabdomyosarcoma, oesophageal cancer,stomach cancer, biliary tract cancer, renal carcinoma, thyroidcarcinoma. Compounds of the invention may be administered prior to,concomitantly with, or following administration of other anticancertreatments such as radiation therapy or chemotherapy. Suitablecytostatic chemotherapy compounds include, but are not limited to (i)antimetabolites, such as cytarabine, fludarabine,5-fluoro-2′-deoxyuiridine, gemcitabine, hydroxyurea or methotrexate;(ii) DNA-fragmenting agents, such as bleomycin, (iii) DNA-crosslinkingagents, such as chlorambucil, cisplatin, cyclophosphamide or nitrogenmustard; (iv) intercalating agents such as' adriamycin (doxorubicin) ormitoxantrone; (v) protein synthesis inhibitors, such as L-asparaginase,cycloheximide, puromycin or diphteria toxin; (Vi) topoisomerase Ipoisons, such as camptothecin or topotecan; (vii) topoisomerase IIpoisons, such as etoposide (VP-16) or teniposide; (viii)microtubule-directed agents, such as colcemid, colchicine, paclitaxel,vinblastine or vincristine; (ix) kinase inhibitors such as flavopiridol,staurosporin, STI571 (CPG 57148B) or UCN-01 (7-hydroxystaurosporine);(x) miscellaneous investigational agents such as thioplatin, PS-341,phenylbutyrate, ET-18-OCH₃, or farnesyl transferase inhibitors(L-739749, L-744832); polyphenols such as quercetin, resveratrol,piceatannol, epigallocatechine gallate, theaflavins, flavanols,procyanidins, betulinic acid and derivatives thereof; (xi) hormones suchas glucocorticoids or fenretinide; (xii) hormone antagonists, such astamoxifen, finasteride or LHRH antagonists. In a particular embodiment,compounds of the present invention are coadministered with a cytostaticcompound selected from the group consisting of cisplatin, doxorubicin,taxol, taxotere and mitomycin C.

Another class of active compounds which can be used in the presentinvention are those which are able to sensitize for or induce apoptosisby binding to death receptors (“death receptor agonists”). Such agonistsof death receptors include death receptor ligands such as tumor necrosisfactor a (TNF-α), tumor necrosis factor ß (TNF-ß, lymphotoxin-α), LT-ß(lymphotoxin-ß), TRAIL (Apo2L, DR4 ligand), CD95 (Fas, APO-1) ligand,TRAMP (DR3, Apo-3) ligand, DR6 ligand as well as fragments andderivatives of any of said ligands. In a particular embodiment, thedeath receptor ligand is TNF-α. In another particular embodiment thedeath receptor ligand is Apo2L/TRAIL. Furthermore, death receptorsagonists comprise agonistic antibodies to death receptors such asanti-CD95 antibody, anti-TRAIL-R1 (DR4) antibody, anti-TRAIL-R2 (DR5)antibody, anti-TRAIL-R3 antibody, anti-TRAIL-R4 antibody, anti-DR6antibody, anti-TNF-R1 antibody and anti-TRAMP (DR3) antibody as well asfragments and derivatives of any of said antibodies.

For the purpose of sensitizing cells for apoptosis, the compounds of thepresent invention can be also used in combination with radiationtherapy. The phrase “radiation therapy” refers to the use ofelectromagnetic or particulate radiation in the treatment of neoplasia.Radiation therapy is based on the principle that high-dose radiationdelivered to a target area will result in the death of reproducing cellsin both tumor and normal tissues. The radiation dosage regimen isgenerally defined in terms of radiation absorbed dose (rad), time andfractionation, and must be carefully defined by the oncologist. Theamount of radiation a patient receives will depend on variousconsideration including the location of the tumor in relation to otherorgans of the body, and the extent to which the tumor has spread.Examples of radiotherapeutic agents are provided in, but not limited to,radiation therapy and is known in the art (Hellman, Principles ofRadiation Therapy, Cancer, in Principles I and Practice of Oncology,24875 (Devita et al., 4th ed., vol 1, 1993). Recent advances inradiation therapy include three-dimensional conformal external beamradiation, intensity modulated radiation therapy (IMRT), stereotacticradiosurgery and brachytherapy (interstitial radiation therapy), thelatter placing the source of radiation directly into the tumor asimplanted “seeds”. These newer treatment modalities deliver greaterdoses of radiation to the tumor, which accounts for their increasedeffectiveness when compared to standard external beam radiation therapy.

Ionizing radiation with beta-emitting radionuclides is considered themost useful for radiotherapeutic applications because of the moderatelinear energy transfer (LET) of the ionizing particle (electron) and itsintermediate range (typically several millimeters in tissue). Gamma raysdeliver dosage at lower levels over much greater distances. Alphaparticles represent the other extreme, they deliver very high LETdosage, but have an extremely limited range and must, therefore, be inintimate contact with the cells of the tissue to be treated. Inaddition, alpha emitters are generally heavy metals, which limits thepossible chemistry and presents undue hazards from leakage ofradionuclide from the area to be treated. Depending on the tumor to betreated all kinds of emitters are conceivable within the scope of thepresent invention. Furthermore, the present invention encompasses typesof non-ionizing radiation like e.g. ultraviolet (UV) radiation, highenergy visible light, microwave radiation (hyperthermia therapy),infrared (IR) radiation and lasers. In a particular embodiment of thepresent invention UV radiation is applied.

Compounds of the invention inhibit angiogenesis and are therefore usefulin the treatment of diseases or conditions mediated by angiogenesis suchas tumors, in particular solid tumors such as colon, lung, pancreatic,ovarian, breast and glioma. Furthermore, compounds of the invention areuseful for treating macular degeneration e.g. wet age-related maculardegeneration. Compounds of the invention are also useful for treatinginflammatory/immune diseases such as Crohn's, inflammatory boweldisease, Sjogren's syndrome, asthma, organ transplant rejection,systemic lupus erythmatoses, rheumatoid arthritis, psoriatic arthritis,psoriasis and multiple sclerosis. Compounds of the invention are alsouseful as a depilatory.

The invention also includes pharmaceutical compositions or medicamentscontaining the compounds of the invention and a therapeutically inertcarrier, diluent or excipient, as well as methods of using the compoundsof the invention to prepare such compositions and medicaments.Typically, the compounds of the invention used in the methods of theinvention are formulated by mixing at ambient temperature at theappropriate pH, and at the desired degree of purity, withphysiologically acceptable carriers, i.e., carriers that are non-toxicto recipients at the dosages and concentrations employed into agalenical administration form. The pH of the formulation depends mainlyon the particular use and the concentration of compound, but may rangefrom about 3 to about 8. A particular formulation is an acetate bufferat pH 5. The compounds for use herein may be in a sterile formulation.The compound may be stored as a solid composition, although lyophilizedformulations or aqueous solutions are acceptable.

The composition of the invention will be formulated, dosed, andadministered in a fashion consistent with good medical practice. Factorsfor consideration in this context include the particular disorder beingtreated, the particular mammal being treated, the clinical condition ofthe individual patient, the cause of the disorder, the site of deliveryof the agent, the method of administration, the scheduling ofadministration, and other factors known to medical practitioners. The“effective amount” of the compound to be administered will be governedby such considerations, and is the minimum amount necessary to decreasehedgehog pathway signaling or else is the minimum amount necessary tocause reduction in size, volume or mass of a tumor that is responsive tohedgehog signaling, or a reduction in the increase in size, volume ormass of such a tumor relative to the increase in the absence ofadministering the compound of the invention. Alternatively “effectiveamount” of the compound means the amount necessary to reduce the numberof malignant cells or the rate in increase of the number of malignantcells. Alternatively, “effective amount” is the amount of the compoundof the invention required to increase survival of patients afflictedwith an anti-hedgehog pathway sensitive tumor. Such amount may be belowthe amount that is toxic to normal cells, or the mammal as a whole. Withrespect to non-malignant indications, “effective amount” means theamount of compound of the invention required to decrease severity of theparticular indication or symptoms thereof.

Generally, the initial pharmaceutically effective amount of the compoundof the invention administered parenterally per dose will be in the rangeof about 0.01 to about 100 mg/kg, for example about 0.1 to about 20mg/kg of patient body weight per day, for example about 0.3 to about 15mg/kg/day. Oral unit dosage forms, such as tablets and capsules, maycontain from about 25 to about 1000 mg of the compound of the invention.

The compound of the invention may be administered by any suitable means,including oral, topical, transdermal, parenteral, subcutaneous, rectal,intraperitoneal, intrapulmonary, and intranasal, and, if desired forlocal treatment, intralesional administration. Parenteral infusionsinclude intramuscular, intravenous, intraarterial, intraperitoneal, orsubcutaneous administration. An example of a suitable oral dosage formis a tablet containing about 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg ofthe compound of the invention compounded with about 90-30 mg anhydrouslactose, about 5-40 mg sodium croscarmellose, about 5-30 mgpolyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate.The powdered ingredients are first mixed together and then mixed with asolution of the PVP. The resulting composition can be dried, granulated,mixed with the magnesium stearate and compressed to tablet form usingconventional equipment. An aerosol formulation can be prepared bydissolving the compound, for example 5-400 mg, of the invention in asuitable buffer solution, e.g. a phosphate buffer, adding a tonicifier,e.g. a salt such sodium chloride, if desired. The solution is typicallyfiltered, e.g. using a 0.2 micron filter, to remove impurities andcontaminants. Topical formulations include ointments, creams, lotions,powders, solutions, pessaries, sprays, aerosols and capsules. Ointmentsand creams may be formulated with an aqueous or oily base with theaddition of suitable thickening and/or gelling agents and/or solvents.Such bases may include water and/or an oil such a liquid paraffin or avegetable oil such as arachis oil or castor oil or a solvent such as apolyethylene glycol. Thickening agents which may be used include softparaffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols,microcrystalline wax and beeswax. Lotions may be formulated with anaqueous or oily base and may contain one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents or thickeningagents. Powders for external application may be formed with the aid ofany suitable powder base e.g. talc, lactose or starch. Drops may beformulated with an aqueous or non-aqueous base also comprising one ormore dispersing agents, solubilizing agents or suspending agents.

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention. Abbreviations used herein are as follows:

BuOH: butanol;DIPEA: diisopropylethylamine;

DMA: NN-dimethylacetamide;

DMAP: 4-dimethylaminopyridine;DME: 1,2-dimethoxyethane;DMF: dimethylformamide;EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;HATU: O-(7-Azobenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate;HPLC: high pressure liquid chromatographyMPLC: medium pressure liquid chromatography

NBS: N-Bromosuccinimide; TEA: Triethylamine;

TASF: tris(dimethylamino)sulfonium difluorotrimethylsilicate;THF: tetrahydrofuran;

EtOH: Ethanol; MeOH: Methanol;

□L: microlitre

All reagents were obtained commercially unless otherwise noted.Reactions were performed using oven-dried glassware under an atmosphereof nitrogen. Air and moisture sensitive liquids and solutions weretransferred via syringe or stainless steel cannula. Organic solutionswere concentrated under reduced pressure (ca. 15 mm Hg) by rotaryevaporation. Unless otherwise noted all solvents used were obtainedcommercially. Chromatographic purification of products was accomplishedby use of an Isco CombiFlash Companion and media. Reaction times aregiven for illustration only. The course of reactions was followed bythin-layer chromatography (TLC) and liquid chromatography-massspectrometry (LC-MS). Thin-layer chromatography (TLC) was performed onEM Science silica gel 60 F₂₅₄ plates (250 μm). Visualization of thedeveloped chromatogram was accomplished by fluorescence quenching. LC-MSwere acquired with a Shimadzu 10AD LC on a Phenomenex column (50×4.6 mm,5 μm) operating at 3 mL/min. A Shimadzu SPD-10A detector monitoring at214 and 254 nm was used. Single quadrupole mass spectrometry wasperformed on an Applied Biosystems mass spectrometer. Nuclear magneticresonance (NMR) spectra were acquired on a Varian Inova spectrometeroperating at 400 MHz for ¹H and are referenced internally totetramethylsilane (TMS) in parts per million (ppm). Data for ¹H NMR arerecorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet;bs, broad singlet; d, doublet; t, triplet; q, quartet; quint, quintet;sext, sextet; hept, heptet; m, multiplet; bm, broad multiplet), andintegration. The structure and purity of all final products wereassessed by at least one of the following techniques: LC-MS, NMR, TLC.

Example 1 General Procedure

Compounds of examples 2-51 were prepared according to the followinggeneral procedures.

A: Suzuki Coupling Procedure

2 M aq. Potassium carbonate (5.0 eq) and 4:1 toluene:ethanol mixture(2.5 mL) were added to a microwave vial charged with the appropriateboronate ester (2.6 eq), aryl halide (0.35 mmol, 1.0 eq), and Pd(PPh₃)₄(0.04 eq). The vial was sealed and heated with stirring in the microwaveto 160° C. for ten minutes. The solution was poured onto 2 M aq. Sodiumhydroxide (20 mL), extracted with ethyl acetate (2×20 mL), dried(MgSO₄), and concentrated. Purification of the crude product bychromatography on silica gel (conditions given below) afforded thedesired product.

B: Negishi Coupling Procedure

Aryl zinc bromide (0.5 M in THF, 2.5 eq) was added to an oven-driedmicrowave vial charged with the appropriate aryl halide (1.0 eq) andPd(PPh₃)₄ (0.04 eq). The vial was sealed and heated with stirring in themicrowave to 140° C. for 10 minutes. The crude reaction mixture wasconcentrated and purified by chromatography on silica gel (conditionsgiven below) to afford the desired product.

C: Iron Reduction of Aryl Nitro Group

The appropriate nitro aryl (1 mmol, 1 eq) in AcOH/EtOH (1:1, 0.42 M) wasadded slowly to a solution of Iron powder (6.0 eq) in AcOH/EtOH (1:2, 2M) at 60° C. The solution was stirred at 70° C. for 30-60 minutes. Thereaction mixture was cooled to 23° C., filtered through celite, washedwith ethyl acetate, and concentrated. The oily residue was dissolved inethyl acetate (30 mL), washed with saturated aq. NaHCO₃ (2×15 mL) andwater (2×10 mL), dried (MgSO₄), and concentrated. The oily residue wasused with out further purification.

D: Amide Bond Formation

Acid chloride (1.05-1.1 eq) was added to a solution of aniline (1.0 eq)and TEA (1.1-1.5 eq) in methylene chloride at the indicated temperature.The solution was stirred for 0.5-3 hours, poured onto saturated aq.NaHCO₃, extracted twice with methylene chloride, dried (MgSO₄), andconcentrated. Purification of the crude product by chromatography onsilica gel (conditions given below) afforded the desired product.

E: EDC Amide Bond Formation

Carboxylic acid (1.1 eq) was added to a solution of aniline (1.0 eq) andEDC (1.4 eq) in methylene chloride (0.7 M in aniline). The solution wasstirred at 23° C. for 2 hours, poured onto a 1:1 mixture of saturatedaq. NH₄Cl and water, extracted twice with methylene chloride, dried(MgSO₄), and concentrated. Purification of the crude product bychromatography on silica gel (conditions given below) afforded thedesired product.

F: Addition of Amines to 2-Chloropyridine

-   NHRR′=ethanolamine, analine, benzylamine, 2-methylpropylamine,    N-methylpiperazine, morpholine, 2-morpholinoethylamine

Primary or secondary amine (5 eq) in either BuOH or a mixture ofBuOH/ethylene glycol was heated to 170 to 220° C. for 20 min in a sealedtube. The BuOH was removed under reduced pressure. In cases whereethylene glycol was used, the reaction was diluted with water, and theproduct was extracted into ethyl acetate, dried (MgSO₄), andconcentrated. The crude residue was purified by reverse phase HPLC toafford the desired product.

G: Amide Bond Coupling with HATU

Aniline (1.0 eq) was added to a mixture of carboxylic acid (1.1 eq),HATU (1.1 eq) and DIPEA (2 eq) in DMF (0.1-0.2 M). After stirringovernight, the reaction mixture was diluted with 0.1 N sodium hydroxideor saturated NaHCO₃, extracted into ethyl acetate and the combinedorganic layers were washed with brine. The organic layer was dried(MgSO₄), concentrated and the crude mixture was purified by reversephase HPLC.

H: Preparation of Sulfonamide Benzoic Acids

Chlororsulfonylbenzoic acid (1.0 eq) was added to a solution of amine(1.1 eq) in 10-20% DIPEA/methanol (1 M) at 4° C. After 1 h, the reactionmixture was concentrated, and the crude residue was purified by reversephase HPLC.

I: Stannylation of 2-Pyridyl Triflates

A solution of tetrakis-triphenylphosphinepalladium (0.04 eq.) in toluene(1 mL) was added to degassed solution of aryltriflate (1 eq),bis-trialkyltin (1.05 eq), and lithium chloride (3 eq) in dioxane.Heated to reflux for 2 hours, cooled to 23° C., diluted with ethylacetate, washed with 10% NH₄OH_((aq)) and brine, dried (MgSO₄) andconcentrated. The crude material was used without further purification.

J: Stannylation of Substituted Pyridines

n-Butyl lithium (6 eq, 2.5 M in hexanes) was added dropwise to asolution of dimethylaminoethanol (3 eq) in hexane at 0° C. The solutionwas stirred at 0° C. for thirty minutes before dropwise addition of thesubstituted pyridine (1 eq). The solution was stirred at 0° C. for anadditional hour, then cooled to −78° C. A solution of trialkyltin inhexane was added dropwise. The solution was stirred at −78° C. forthirty minutes, warmed to 0° C., quenched with water, extracted twicewith ether, dried (MgSO₄), and concentrated.

K: Stille Coupling

Palladium catalyst (0.02 eq) was added to a degassed solution ofaryliodide (1 eq), arylstannane (2 eq), and triphenylphosphine (0.16 eq)in NMP. Heated in the microwave to 130° C. for 15 minutes. The reactionmixture was diluted with ethylacetate, washed with 10% NH₄OH_((aq)) andbrine, dried (MgSO₄), concentrated and purified by silica gelchromatography.

L: Synthesis of Alkylethers

A solution of hydroxypyridine (1 eq), alkyliodide (excess), and cesiumcarbonate in NMP was heated in the microwave to 100° C. for ten minutes.The reaction mixture was diluted with ethylacetate, washed with 10%NH₄OH_((aq)) and brine, dried (MgSO₄), concentrated and purified bysilica gel chromatography.

M: Methyl Ester Saponification

The methyl ester (1 eq) was hydrolyzed with LiOH (2 eq) in 50/50THF/water mix. Upon completion of the reaction the THF was evaporatedunder reduced pressure and the solution is acidified with HCl to pH 2.The resultant solid was filtered and dried to give the pure acid.

N: Bromination in the Presence of a Free Acid Functionality

The paramethylbenzoic acid (1 eq) was combined with Benzoyl Peroxide(0.1 eq) and N-Bromosuccinimde (0.9 eq) in a solution of 5% AcOH inBenzene and heated in the microwave at 120° C. for 5-15 minutes. Theproduct was separated from the starting material and di-bromo productvia ISCO flash chromatography with an ethyl acetate (with 1% AcOH) andhexanes solvent system.

O: Sodium Methanesulfinate Displacement of Bromine

To the bromine starting material (1 eq) was added sodiummethanesulfinate (2 eq) in DMF and heated to 120° C. in the microwavefor 5 minutes. Alternatively, the reaction was heated to 60° C. in anoil bath for several hours until completed. Reaction mixture wasconcentrated under reduced pressure and extracted in ethyl acetate andwater. The organic layer was dried over Magnesium Sulfate, filtered andconcentrated in vacuo to yield generic methylsulfone.

P: Amine Displacement of Bromine

To the bromo starting material (1 eq) was added appropriate amine (3 eq)in either DMSO or BuOH and stirred at room temperature until complete.For less nucleophilic amines or anilines, the reactions were forced tocompletion using microwave conditions ranging from 150-170° C. for 15minutes. Crude reactions were concentrated to dryness and eitherextracted with ethyl acetate and saturated bicarbonate if the reactionresulted in an intermediate or purified via HPLC if the reactionresulted in a final product.

Q: Thiol Displacement of Halogen

The paramethylbromo benzoate (1 eq) was treated with Potassium (orCesium) Carbonate (1.5 eq) and appropriate thiol derivative (1.1 eq) inDMF (or CH₃CN) and stirred overnight at room temperature. The DMF wasevaporated in vacuo and the reaction was extracted with ethyl acetateand water. The organic layer was dried over Magnesium Sulfate, filteredand concentrated to yield the thiol or derivatized thiol compound.

R: Oxone Oxidation

Derivatized thiol (1 eq) was dissolved in MeOH while Oxone (2 eq) wasseparately dissolved in half the amount of water. Once all the oxone wasdissolved, the solution was added to the thiol in MeOH solution at onceand stirred until complete. The MeOH was evaporated in vacuo and theremaining water was extracted twice with Ethyl Acetate. The organiclayer was dried over Magnesium Sulfate and concentrated to yield thesulfone.

S: Thiolysis of Epoxides at Alumina Surfaces

A mixture of epoxides (1.0 eq), thiophenol (1.5 eq) and neutral aluminumoxide (˜70 eq) in diethyl ether was stirred for 3 h at room temperaturewhile being monitored by TLC. The reaction mixture was filtered throughCelite, washed with ethyl acetate and concentrated. Purified by silicagel chromatography (0-40% ethyl acetate/hexane) to yield ifβ-hydroxysulfide product.

T: Conversion of Nitrile Group to Carboxylic Acid

A solution of benzonitrile (1.0 eq) and sodium hydroxide (2.0 eq) in H₂Owas heated to 120° C. for 2 h. The reaction mixture was cooled to roomtemperature and acidified with HCl to pH 2. The resulting solid wasfiltered to afford the pure acid product.

U. Alkylation of Phenols

The phenol was dissolved in DMF (1.0 ml). Cesium carbonate (1.0 eq.) andan alkyl bromide or alkyl iodide (1.0 to 2.0 eq.) were added, and thereaction was stirred at room temperature for 18 hrs or 50° C. for 1 to24 hours. The reaction was quenched in water, and extracted with ethylacetate twice. The organic extracts were washed with water once, brineonce, dried with MgSO₄, and evaporated to a crude oil which was purifiedon reverse phase HPLC.

V. Amide Bond Formation with an Acid Chloride and an Aniline

The aniline was dissolved in THF (1.5 ml) and dichloromethane (1.5 ml).MP-Carbonate (1.5 eq.) and an acid chloride (1.1 eq.) were added, andthe solution was stirred at room temperature for 18 hours. The reactionwas diluted with methanol and dichloromethane, and filtered to removethe MP-Carbonate. The mother liquors were evaporated to a solid andpurified by reverse phase HPLC.

W. Amidine Formation from an Imidate

A solution of freshly formed imidate in methanol was treated with aprimary or secondary amine (1.5 eq.) at room temperature for 18 hours.The methanol was removed on a rotary evaporator and the residue purifiedby reverse phase HPLC.

Example 26-(2-morpholinoethylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) and2-morpholinoethylamine in butanol (0.5 mL). The crude reaction waspurified by reverse phase HPLC to yield6-(2-morpholinoethylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamideas a white solid. MS (Q1) 438.3 (M)⁺.

Example 3N,N-(4-Chloro-3-(pyridin-2-yl)phenyl)-bis[6-(trifluoromethyl)-2-methylpyridine-3]-carboxamide

Procedure B was performed with 2-pyridylzinc bromide (4 mL, 2.0 mmol,0.5 M in THF) and 3-bromo-4-chloro-nitrobenzene (236 mg, 1.0 mmol).Purified by chromatography on silica gel (10% ethyl acetate/hexanes) toyield 2-(2-chloro-5-nitrophenyl)pyridine as a light yellow solid.

Procedure C was performed with 2-(2-chloro-5-nitrophenyl)pyridine (122mg, 0.52 mmol) to yield 4-chloro-3-(pyridin-2-yl)aniline as a lightyellow solid, which was used without further purification.

Procedure D was performed using 4-chloro-3-(pyridin-2-yl)aniline (40 mg,0.2 mmol). The crude residue was purified by silica gel chromatography(15-60% ethyl acetate/hexanes) to yieldN,N-(4-Chloro-3-(pyridin-2-yl)phenyl)-bis[6-(trifluoromethyl)-2-methylpyridine-3]-carboxamideas an oily residue: TLC R_(f)=0.42 (35% ethyl acetate/hexanes); ¹H NMR(CDCl₃, 400 MHz) δ 8.72 (m, 1H), 7.84 (d, 2H0, 7.77 (dd, 1H), 7.68 (m,1H), 7.57 (d, 1H), 7.51 (m, 3H), 7.33 (m, 1H), 7.12 (dd, 1H), 2.78 (s,6H); MS (Q1) 579 (M)⁺.

Example 4 N-(4-Chloro-3-(pyridin-3-yl)phenyl)-3,5-dimethoxybenzamide

4-Chloro-3-(pyridin-2-yl)aniline (40 mg, 0.2 mmol) was used in procedureD with 3,5-dimethoxybenzoyl chloride (43 mg, 0.216 mmol) at 23° C. for 2hours. The crude residue was purified by crystallization(CH₂Cl₂/hexanes) to yieldN-(4-chloro-3-(pyridin-3-yl)phenyl)-3,5-dimethoxybenzamide as anoff-white solid: TLC R_(f)=0.30 (15% ethyl acetate/hexanes); ¹H NMR(CDCl₃, 400 MHz) δ 8.72 (m, 1H), 7.91 (m, 1H), 7.88 (dd, 1H), 7.78 (m,2H), 7.74 (dd, 1H), 748 (d, 1H), 7.35 (m, 1H), 6.96 (d, 2H), 6.62 (t,1H), 3.82 (s, 6H); MS (Q1) 369 (M)⁺.

Example 55-Acetyl-N-(4-chloro-3-(pyridin-2-yl)phenyl)thiophene-2-carboxamide

4-Chloro-3-iodoaniline (2.5 g, 9.88 mmol) was used in Procedure E with5-acetylthiophene-2-carboxylic acid (1.85 g, 10.8 mmol) at 23° C. for 2hours. The crude material was purified by silica gel chromatography(20-100% ethyl acetate/hexanes) to yield5-Acetyl-N-(4-chloro-3-iodophenyl)thiophene-2-carboxamide as a yellowsolid.

5-Acetyl-N-(4-chloro-3-iodophenyl)thiophene-2-carboxamide (202 mg, 0.5mmol) was used in Procedure B with 2-pyridylzincbromide (2.5 mL, 1.25mmol, 0.5 M in THF). Purified by silica gel chromatography (10-100%ethyl acetate/hexanes) to yield5-acetyl-N-(4-chloro-3-(pyridin-2-yl)phenyl)thiophene-2-carboxamide as ayellow solid: TLC R_(f)=0.19 (50% ethyl acetate/hexanes); ¹H NMR (CDCl₃,400 MHz) δ 8.96 (bs, 1H), 8.67 (d, 1H), 7.79 (dt, 1H), 7.68 (m, 3H),7.61 (d, 1H), 7.58 (d, 1H), 7.37 (d, 1H), 7.32 (m, 1H), 2.58 (s, 3H); MS(Q1) 357.0 (M)⁺.

Example 6N-(4-Chloro-3-(3-methylpyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide

N-(4-Chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide(142 mg, 0.32 mmol) was used in Procedure B with 6-methyl-2-pyridylzincbromide (1.75 mL, of a 0.5 M in THF). Purified by silica gelchromatography (5-100% Ethyl acetate/Hexanes) to yieldN-(4-chloro-3-(3-methylpyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamideas a white solid: TLC R_(f)=0.23 (30% ethyl acetate/hexanes); ¹H NMR(CDCl₃, 400 MHz) δ 8.81 (bs, 1H), 7.95 (dd, 1H), 7.67 (m, 3H), 7.53 (t,2H), 7.38 (d, 1H), 7.07 (d, 1H), 2.71 (s, 3H), 2.43 (s, 3H); MS (Q1)406.1 (M)⁺.

Example 7N-(4-Chloro-3-(5-methylpyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide

N-(4-Chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide(150 mg, 0.34 mmol) was used in Procedure B with 4-methyl-2-pyridylzincbromide (1.7 mL of a 0.5 M in THF). Purified by silica gelchromatography (5-75% Ethyl acetate/Hexanes) to yieldN-(4-chloro-3-(5-methylpyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamideas a white solid: TLC R_(f)=0.23 (35% ethyl acetate/hexanes); ¹H NMR(CDCl₃, 400 MHz) δ 10.62 (bs, 1H), 8.12 (dd, 1H), 7.89 (d, 1H), 7.58 (d,1H), 7.47 (m, 3H), 7.18 (d, 1H), 6.89 (d, 1H), 2.62 (s, 3H), 2.38 (s,3H); MS (Q1) 406.3 (M)⁺.

Example 85-Acetyl-N-(4-chloro-3-(5-methylpyridin-2-yl)phenyl)thiophene-2-carboxamide

5-Acetyl-N-(4-chloro-3-iodophenyl)thiophene-2-carboxamide (203 mg, 0.5mmol), was used in Procedure B with 4-methyl-2-pyridylzinc bromide (2.5mL, 1.25 mmol, 0.5 M in THF). Purified by silica gel chromatography(30-100% ethyl acetate/hexanes) to yield5-acetyl-N-(4-chloro-3-(5-methylpyridin-2-yl)phenyl)thiophene-2-carboxamideas a yellow solid: TLC R_(f)=0.25 (50% ethyl acetate/hexanes); ¹H NMR(CDCl₃, 400 MHz) δ 9.52 (bs, 1H), 8.51 (d, 1H), 7.60 (m, 4H), 7.39 (s,1H), 7.29 (d, 1H), 7.14 (d, 1H), 2.55 (s, 3H), 2.42 (s, 3H); MS (Q1) 371(M)⁺.

Example 9N-(4-Chloro-3-(4-methylpyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide

Procedure B was performed withN-(4-Chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide(440 mg, 1.0 mmol) and 4-methyl-2-pyridylzinc bromide (5 mL of a 0.5 Msolution in THF). The crude residue was purified silica gelchromatography (5-100% Ethyl acetate/Hexanes) to yieldN-(4-chloro-3-(4-methylpyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamideas a white solid: TLC R_(f)=0.43 (35% ethyl acetate/hexanes); ¹H NMR(CDCl₃, 400 MHz) δ 10.39 (bs, 1H), 8.11 (dd, 1H), 7.87 (s, 1H), 7.61 (d,1H), 7.59 (d, 1H), 7.49 (m, 3H), 2.66 (s, 3H), 2.21 (s, 3H); MS (Q1)406.1 (M)⁺.

Example 10N-(4-chloro-3-(6-methylpyridin-2-yl)phenyl)-3,5-dimethylisoxazole-4-carboxamide

4-Chloro-3-iodoaniline (1.01 g, 4 mmol) was used in procedure E with3,5-dimethyl-4-isoxazolecarboxylic acid (0.565 g, 4 mmol), EDC (1.32 g,6.8 mmol), TEA (0.5 mL), DMAP (50 mg, 0.4 mmol) at 23° C. for overnight.The crude reaction was purified by silica gel chromatography (0-15%ethyl acetate/CH₂Cl₂) to yield3,5-dimethyl-N-(4-chloro-3-iodophenyl)isoxazole-4-carboxamide as a whitesolid.

Procedure B was performed with3,5-dimethyl-N-(4-chloro-3-iodophenyl)isoxazole-4-carboxamide (190 mg,0.5 mmol) and 3-methyl-2-pyridylzinc bromide (2.5 mL of a 0.5 M solutionin THF). The crude reaction was purified by silica gel chromatography(5-100% Ethyl acetate/Hexanes) to yieldN-(4-chloro-3-(6-methylpyridin-2-yl)phenyl)-3,5-dimethylisoxazole-4-carboxamideas a white solid: TLC R_(f)=0.43 (50% ethyl acetate/hexanes); ¹H NMR(CDCl₃, 400 MHz) δ 8.52 (bs, 1H), 7.68 (m, 2H), 7.48 (m, 3H), 2.70 (s,3H), 2.49 (s, 3H), 2.21 (s, 3H); MS (Q1) 342.3 (M)⁺.

Example 11N-(4-chloro-3-(pyridin-2-ylamino)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide

N-(4-Chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide(220 mg, 0.5 mmol), 2-aminopyridine (40 mg, 0.42 mmol), potassiumt-butoxide (66 mg, 0.59 mmol), Pd₂(dba)₃ (20 mg, 0.21 mmol), dppf (24mg, 0.042 mmol) in toluene (2.1 mL) were heated to 100° C. for 1.5 days.The solution was cooled to 23° C., diluted with ether, filtered throughcelite, washed with ethyl acetate, and concentrated. Purified by reversephase HPLC to yieldN-(4-chloro-3-(pyridin-2-ylamino)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamideas a white solid: ¹H NMR (CDCl₃, 400 MHz) δ 11.53 (s, 1H), 9.68 (s, 1H),8.05 (m, 2H), 7.85 (m, 2H), 7.55 (d, 1H), 7.26 (d, 1H), 7.13 (dd, 1H),6.91 (t, 1H), 6.88 (d, 1H), 2.75 (s, 3H); MS (Q1) 407.0 (M)⁺.

Example 12N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-methylpiperazin-1-yl)pyridine-3-carboxamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) andN-methylpiperazine in butanol (0.5 mL). The crude reaction was purifiedby reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-methylpiperazin-1-yl)pyridine-3-carboxamideas a white solid. MS (Q1) 408.4 (M)⁺.

Example 13N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(isobutylamino)pyridine-3-carboxamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) and2-methylpropylamine in butanol (0.5 mL). The crude reaction was purifiedby reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(isobutylamino)pyridine-3-carboxamideas a white solid. MS (Q1) 381.1 (M)⁺.

Example 14N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-morpholinopyridine-3-carboxamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) andmorpholine in butanol (0.5 mL). The crude reaction was purified byreverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-morpholinopyridine-3-carboxamideas a white solid. MS (Q1) 401.3 (M)⁺.

Example 156-(benzylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) andbenzylamine in butanol (0.5 mL). The crude reaction was purified byreverse phase HPLC to yield6-(benzylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamideas a white solid. MS (Q1) 415.1 (M)⁺.

Example 16N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(phenylamino)pyridine-3-carboxamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) andanaline in butanol (0.5 mL). The crude reaction was purified by reversephase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(phenylamino)pyridine-3-carboxamideas a white solid. MS (Q1) 401.0 (M)⁺.

Example 17N-(4-Chloro-3-(pyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide

Procedure C was performed with 1-chloro-2-iodo-4-nitrobenzene (283 mg, 1mmol) to produce 4-chloro-3-iodoaniline which was used without furtherpurification.

Procedure D was performed with 4-chloro-3-iodoaniline (225 mg, 0.889mmol) and 6-(trifluoromethyl)-2-methylpyridine-3-carbonyl chloride (237mg, 0/93 mmol, 1.05 eq) at 0° C. for 30 minutes. The crude residue waspurified by silica gel chromatography (2-50% ethyl acetate/hexanes) toyieldN-(4-chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamideas a white solid.

Procedure B was performed usingN-(4-Chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide(88 mg, 0.2 mmol) with 2-pyridylzinc bromide (1 mL, 0.5 mmol, 0.5 M inTHF). Purified by silica gel chromatography (10-80% ethylacetate/hexanes) to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamideas a yellow solid: TLC R_(f)=0.28 (35% ethyl acetate/hexanes); TLCR_(f)=0.28 (35% ethyl acetate/hexanes); ¹H NMR (CDCl₃, 400 MHz) 8.88(bs, 1H), 8.41 (d, 1H), 7.96 (dd, 1H), 7.74 (m, 4H), 7.52 (d, 1H), 7.22(m, 1H), 2.75 (s, 3H); MS (Q1) 392 (M)⁺.

An alternative synthetic procedure is as follows. 75 g (435 mmol) of2-chloro-5-nitroaniline was added to a solution of water (600 mL) andcone. sulfuric acid (60 mL) in a 3 L 3-neck flask equipped formechanical stirring. The solution was cooled to 0° C. and a solution ofsodium nitrite (34.2 g, 496 mmol) in water (130 mL) was added slowly.The mixture was stirred for ½ hr. and then a solution of potassiumiodide (130 g, 783 mmol) in water (520 mL) was added dropwise over ½ hrkeeping the temperature below 15° C. The solution was stirred for 2 hr,then extracted with EtOAc (3×500 mL). The combined organic extracts werewashed with sat. Na₂S₂O₃ (2×500 mL), dried (Na₂SO₄), and concentrated.The crude iodide was dissolved in hot iPrOH (500 mL) and hexanes (200mL) were added. The reaction was allowed to cool with stirring and theproduct was collected by suction filtration after stirring at 0° C. for2 hr yielding 90 g (318 mmol, 73%) 2-chloro-5-nitro-iodobenzene as alight tan crystalline solid.

The 2-chloro-5-nitro-iodobenzene (5 g, 17.6 mmol) was dissolved in 5 mLDMA in an oven dried flask and a 0.5M solution of 2-pyridylzincbromide(53 mL, 26.5 mmol, 0.5 M in THF) was added. The solution was degassedwith N₂ for ½ hr., the PPh₃ (0.185 g, 0.7 mmol) and Pd(PPh₃)₄ (0.825 g,0.7 mmol) were added, rinsed in with several mLs THF and the solutionwas degassed for a further 10 min before heating to 60° C. under N₂. Thereaction was complete by TLC in ˜8 h, cooled to RT, and poured into a1:1 mixture of EtOAc/2.5N NaOH (500 mL). This solution was stirred for10 min, passed through a course fritted filter containing celite toremove the solid, and then extracted. The organics were washed withbrine and concentrated to a brown solid. The combined aqueous layerswere backextracted with Et₂O (1×200 mL). This was used to suspend thecrude product, which was extracted with 1N HCl (1×200 mL, 3×100 mL). Thecombined aqueous extracts were cooled to 0° C., diluted with EtOAc (250mL), and made basic with 10N NaOH (100 mL). This solution was separated,the aqueous layer extracted with EtOAc, and the combined organics weredried over Na₂SO₄ and charcoal with stirring. This solution was filteredthrough celite and concentrated to yield pure4-chloro-3-(pyridin-2-yl)nitrobenzene (2.47 g, 10.5 mmol, 60% yield)which was used in the next reaction without further purification.

4-chloro-3-(pyridin-2-yl)nitrobenzene (1.47 g, 6.26 mmol) was suspendedin EtOH (35 mL), and the SnCl₂ (3.87 g; 20.4 mmol) and conc. HCl (5 mL)were added and rinsed in with a further 5 mLs EtOH. The solution wasplaced in a 40° C. oil bath and heated to 60° C. The solution wasstirred at 60° C. for 1½ hr., cooled to RT and diluted with 1 N HCl (100mL). This solution was poured into an Et₂O/1 N HCl solution (100 mL:150mL) and extracted. The aqueous layer was diluted with EtOAc (250 mL),cooled to 0° C., and made basic with 10 N NaOH (50 mL). This solutionwas extracted (EtOAc, 2×), and the combined organics were washed withbrine and dried over Na₂SO₄ and charcoal. Suction filtration throughcelite gave a clear colorless solution which was concentrated to yield4-chloro-3-(pyridine-2-yl)aniline (1.21 g, 5.93 mmol, 94% yield) as acream colored crystalline solid which was used in the next reactionwithout further purification.

6-(trifluoromethyl)-2-methylpyridine-3-carbonyl chloride (1.68 g, 7.51mmol) in 3 mL THF was added dropwise to a solution of4-chloro-3-(pyridine-2-yl)aniline (1.21 g, 5.93 mmol) in THF (15 mL) at0° C. The solution was stirred for 10 min., poured into EtOAc and washedwith saturated aq. NaHCO₃ (2×), and brine. The organics were dried(Na₂SO₄) and concentrated. The crude product was suspended iniPrOAc/Et₂O (10 mL, 1:1), stirred at 0° C. for ½ hr, and collected bysuction filtration to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide(2.04 g, 5.21 mmol, 88% yield) as a white solid: TLC R_(f)=0.28 (35%EtOAc/Hex); ¹H NMR (CDCl₃, 400 MHz) δ 8.88 (bs, 1H), 8.41 (d, 1H), 7.96(dd, 1H), 7.74 (m, 4H), 7.52 (d, 1H), 7.22 (m, 1H), 2.75 (s, 3H); MS(Q1) 392 (M)⁺.

Example 186-(2-hydroxyethylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) andethanolamine in butanol (0.5 mL). The crude reaction was purified byreverse phase HPLC to yield6-(2-hydroxyethylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamideas a white solid. MS (Q1) 369.0 (M)⁺.

Example 19N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(trifluoromethylsulfonyl)benzamide

4-(trifluoromethylthio)benzoic acid (200 mg, 0.9 mmol) was dissolved inwater (2 mL) and acetic acid (4 mL) and treated with potassiumpermanganate (711 mg, 4.5 mmol) at room temperature. The reaction wasallowed to stir for 16 h, diluted with ethyl acetate and washed withwater. The organic layer was dried (MgSO₄) and concentrated to yield4-(trifluoromethylsulfone)benzoic acid.

General procedure G was performed using4-(trifluoromethylsulfone)benzoic acid and4-chloro-3-(pyridin-2-yl)aniline. The crude reaction mixture waspurified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(trifluoromethylsulfonyl)benzamide.MS (Q1) 440.95 (M)⁺.

Example 20N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzamide

General procedure G was performed using 4-(ethylthio)benzoic acid and4-chloro-3-(pyridin-2-yl)aniline to produceN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylthio)benzamide.

A solution of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylthio)benzamide(40 mg, 0.11 mmol) in MeOH (3 mL), cooled to 0° C. was treated withoxone (133 mg, 0.22 mmol), and the ice bath was removed. After 1 h ofstirring, the reaction mixture was concentrated, and the residue wasdissolved in ethyl acetate. The organic solution was washed with water,dried (MgSO₄) and concentrated. The crude reaction mixture was purifiedby reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzamide. MS (Q1)401.0 (M)⁺.

Example 212-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((dimethylamino)methyl)benzamide

General procedure G was used to couple4-(BOC-aminomethyl)-2-chloro-benzoic acid and4-chloro-3-(pyridin-2-yl)aniline to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(BOC-aminomethyl)-benzamidewith. The crude reaction mixture was treated to TFA and trace water for1 h prior to concentrating to dryness to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(aminomethyl)-benzamide.

2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(aminomethyl)benzamide(80 mg, 0.20 mmol) was dissolved in DMF (5 mL) and treated with AcOH (10uL), paraformaldehyde (43 mg, 0.47 mmol), and sodiumtriacetoxyborohydride (125 mg, 0.59 mmol). After stirring for 16 h, thesolvent was evaporated and the residue was dissolved in ethyl acetate.The organic layer was washed with 1 N Sodium hydroxide, dried (MgSO₄)and concentrated. The crude product was purified by reverse phase HPLCto produce2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((dimethylamino)methyl)benzamide. MS (Q1) 400.0 (M)⁺.

Example 22N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(morpholinomethyl)pyridine-3-carboxamide

6-methylnicotinic acid (100 mg 0.14 mmol) was dissolved in 10%AcOH/benzene (1 mL) and treated with NBS (117 mg, 0.18 mmol) andbenzoylperoxide (18 mg, 0.07 mmol). The reaction mixture was heated in asealed microwave reactor at 120° C. for 1 min. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous NaHCO₃, dried(MgSO₄), concentrated and purified by silica gel chromatography to yield6-(bromomethyl)pyridine-3-carboxylic acid.

6-(bromomethyl)pyridine-3-carboxylic acid was coupled to4-chloro-3-(pyridin-2-yl)aniline as described in general procedure E toyield6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide.

6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamidewas dissolved in DMSO (1 mL) treated with morpholine (33 uL) for 1 h.The reaction was concentrated, and the crude residue was purified byreverse phase HPLC to produceN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(morpholinomethyl)pyridine-3-carboxamide.MS (Q1) 409.3 (M)⁺.

Example 23N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide

4-(bromomethyl)benzoic acid was coupled to4-chloro-3-(pyridin-2-yl)aniline as described in general procedure E toyield 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.

4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) wasdissolved in DMSO (0.5 mL) and treated with 2-aminopyridine (59 mg) at150° C. in a sealed microwave reactor for 5 min. The reaction mixturewas concentrated, and the crude residue was purified by reverse phaseHPLC to produce pureN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((pyrimidin-2-ylamino)methyl)benzamide.MS (Q1) 416.3 (M)⁺.

Example 24N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((4-methylpiperazin-1-yl)methyl)pyridine-3-carboxamide

6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamidewas dissolved in 1 mL of DMSO and stirred for 1 h withN-methylpiperazine. The reaction was concentrated, and the crude residuewas purified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((4-methylpiperazin-1-yl)methyl)pyridine-3-carboxamideas a pure product. MS (Q1) 422.3 (M)⁺.

Example 254-((4-acetylpiperazin-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide(85 mg) was dissolved in DMSO (1 mL) and stirred for 1 h withN-acetylpiperazine. The reaction mixture was concentrated, and the cruderesidue was purified by revered phase HPLC to yield4-((4-acetylpiperazin-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 449.1 (M)⁺.

Example 26N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiomorpholinomethyl)benzamide

4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) wasdissolved in DMSO (1 mL) and stirred for 1 h with thiomorpholine. Thereaction mixture was concentrated, and the crude residue was purified byreverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiomorpholinomethyl)benzamide.MS (Q1) 424.0 (M)⁺.

Example 27N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(morpholinomethyl)benzamide

4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) wasdissolved in DMSO (1 mL) and stirred for 1 h with morpholine. Thereaction mixture was concentrated, and the crude residue was purified byreverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(morpholinomethyl)benzamide. MS(Q1) 408.4 (M)⁺.

Example 28N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((piperidin-1-yl)methyl)benzamide

4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) wasdissolved in DMSO (1 mL) and stirred for 1 h with piperidine. Thereaction mixture was concentrated, and the crude residue was purified byreverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((piperidin-1-yl)methyl)benzamide.MS (Q1) 406.4 (M)⁺.

Example 29N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide

4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) wasdissolved in DMSO (1 mL) and stirred for 1 h with methylpiperazine. Thereaction mixture was concentrated, and the crude residue was purified byreverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide. MS (Q1) 421.3 (M)⁺.

Example 30N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((dimethylamino)methyl)benzamide

Procedure G was used to couple BOC-4-(aminomethyl)benzoic acid (48 mg)with 4-chloro-3-(pyridin-2-yl)aniline (35 mg). The crude reactionmixture was treated with TFA (1 mL) containing trace amounts of waterfor 1 h. The reaction mixture was concentrated to yield4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.

4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (80 mg) wasdissolved in DMF (5 mL) and treated with AcOH (10 □L), paraformaldehyde(48 mg), and sodium triacetoxyborohydride (125 mg) for 16 h. Thereaction mixture was concentrated, and the crude residue was dissolvedin ethyl acetate and washed with 1 N sodium hydroxide, dried (MgSO₄) andconcentrated. The crude product was purified by reverse phase HPLC toyieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((dimethylamino)methyl)benzamide.MS (Q1) 365.0 (M)⁺.

Example 31N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-[(2-methylpropyl)aminosulfonyl]-benzamide

Procedure H was performed to couple 3-(chlorosulfonyl)benzoic acid withsec-butyl amine to produce 3-(sec-butylsulfamoyl)benzoic acid which waspurified by reverse phase HPLC.

Procedure G was used to couple 3-(sec-butylsulfamoyl)benzoic acid with4-chloro-3-(pyridin-2-yl)aniline (28 mg) to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-3-[(2-methylpropyl)aminosulfonyl]-benzamide.MS (Q1) 444.0 (M)⁺.

Example 32N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-morpholinylsulfonyl)-benzamide

Procedure H was performed to couple 4-(chlorosulfonyl)benzoic acid withmorpholine to produce 4-(morpholinosulfamoyl)benzoic acid which waspurified by reverse phase HPLC.

Procedure G was used to couple 4-(morpholinosulfamoyl)benzoic acid with4-chloro-3-(pyridin-2-yl)aniline (34 mg) to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-morpholinylsulfonyl)-benzamide.MS (Q1) 458.1 (M)⁺.

Example 33N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(4-morpholinylsulfonyl)-benzamide

Procedure H was performed to couple 3-(chlorosulfonyl)benzoic acid withmorpholine to produce 3-(morpholinosulfamoyl)benzoic acid which waspurified by reverse phase HPLC.

Procedure G was used to couple 3-(morpholinosulfamoyl)benzoic acid with4-chloro-3-(pyridin-2-yl)aniline (25 mg) to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(4-morpholinylsulfonyl)-benzamide.MS (Q1) 458.1 (M)⁺.

Example 34N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-[(2-hydroxyethyl)amino]sulfonyl]-benzamide

Procedure H was performed to couple 4-(chlorosulfonyl)benzoic acid withethanolamine to produce 4-(2-hydroxyethylsulfamoyl)benzoic acid whichwas purified by reverse phase HPLC.

Procedure G was used to couple 4-(2-hydroxyethylsulfamoyl)benzoic acidwith 4-chloro-3-(pyridin-2-yl)aniline (42 mg) to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-[(2-hydroxyethyl)amino]sulfonyl]-benzamide.MS (Q1) 431.9 (M)⁺.

Example 35N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-[(2-hydroxyethyl)amino]sulfonyl]-benzamide

Procedure H was performed to couple 3-(chlorosulfonyl)benzoic acid withethanolamine to produce 3-(2-hydroxyethylsulfamoyl)benzoic acid whichwas purified by reverse phase HPLC.

Procedure G was used to couple 3-(2-hydroxyethylsulfamoyl)benzoic acidwith 4-chloro-3-(pyridin-2-yl)aniline (42 mg) to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-3-[(2-hydroxyethyl)amino]sulfonyl]-benzamide.MS (Q1) 432.0 (M)⁺.

Example 36N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(4-morpholinylsulfonyl)-benzamide

Procedure H was performed to couple 3-(chlorosulfonyl)benzoic acid withpiperazine to produce 3-(N-methylpiperazinosulfamoyl)benzoic acid whichwas purified by reverse phase HPLC.

Procedure G was used to couple 3-(N-methylpiperazinosulfamoyl)benzoicacid with 4-chloro-3-(pyridin-2-yl)aniline (50 mg) to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(4-morpholinylsulfonyl)-benzamide.MS (Q1) 471.0 (M)⁺.

Example 372-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg)and 2-chloro-4-methylsulfonylbenzoic acid to produce2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide.MS (Q1) 421.0 (M)⁺. The product was then dissolved in 1 N HCl solutionfollowed by freebasing with 0.5 N NaOH solution (pH to 11). Theresulting precipitate was filtered and vacuum-dry.

Procedure D may also be used to couple 4-chloro-3-(pyridin-2-yl)anilineand 2-chloro-4-(methylsulfonyl)benzoyl chloride to produce2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamidewhich is collected by suction filtration and the HCl salt is washed withEt₂O (or alternatively with MTBE). This material is freebased usingEtOAc/aq NaHCO₃ and the organics are dried and concentrated to the solidfreebase. This material is then crystallized from acetone:EtOAc (80:20,approx 10 mL/g) which is then finally recrystallized from hot slurry ofiPrOAc.2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamideHCl salt may also be dissolved in distilled water followed by freebasingwith 0.5 N NaOH solution (pH to 11) and filtering and vacuum drying theprecipitate.

Example 38N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(1H-1,2,4-triazol-1-yl)pyridine-3-carboxamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (40 mg)and 6-(1H-1,2,4-triazol-1-yl)pyridine-3-carboxylic acid to produceN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(1H-1,2,4-triazol-1-yl)pyridine-3-carboxamide.MS (Q1) 377.0 (M)⁺.

Example 39N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-[(dimethylamino)sulfonyl]-benzamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg)and 4-[(dimethylamino)sulfonyl]benzoic acid to produceN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-[(dimethylamino)sulfonyl]-benzamide.MS (Q1) 416.0 (M)⁺.

Example 40N-(4-chloro-3-(pyridin-2-yl)phenyl)-5-(methylsulfonyl)thiophene-2-carboxamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (40 mg)and 5-(methylsulfonyl)thiophene-2-carboxylic acid to produceN-(4-chloro-3-(pyridin-2-yl)phenyl)-5-(methylsulfonyl)thiophene-2-carboxamide.MS (Q1) 393.0 (M)⁺.

Example 41N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(aminosulfonyl)-benzamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (30 mg)and 4-carboxybenzenesulfonamide to produceN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(aminosulfonyl)-benzamide. MS (Q1)388.0 (M)⁺.

Example 422,6-dichloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg)and 2,6-dichloronicotinic acid to produce2,6-dichloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide.MS (Q1) 378.1 (M)⁺.

Example 43 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg)and 2-chlorobenzoic acid to produce2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 343.1(M)⁺.

Example 44N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-fluoropyridine-3-carboxamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg)and 2-fluoronicotinic acid to produceN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-fluoropyridine-3-carboxamide. MS(Q1) 328.1 (M)⁺.

Example 45N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-methylthiophene-2-carboxamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg)and 3-methyl-2-thiophenecarboxylic acid to produceN-(4-chloro-3-(pyridin-2-yl)phenyl)-3-methylthiophene-2-carboxamide. MS(Q1) 329.0 (M)⁺.

Example 462-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-5-(methylsulfonyl)benzamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline and2-chloro-5-(methanesulfonyl)benzoic acid to produce2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-5-(methylsulfonyl)benzamide.MS (Q1) 420.95 (M)⁺.

Example 47N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(methylsulfonyl)benzamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline and3-(methanesulfonyl)benzoic acid to produceN-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(methylsulfonyl)benzamide. MS (Q1)387.2 (M)⁺.

Example 482-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg)and 2-aminonicotinic acid to produce2-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide. MS(Q1) 325.2 (M)⁺.

Example 49 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-methoxybenzamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline and4-methoxylbenzoic acid to produceN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-methoxybenzamide. MS (Q1) 341.2(M)⁺.

Example 50 N-benzyl-5-chloro-4-(pyridin-2-yl)thiazol-2-amine

A solution of 2-(Bromoacetyl)pyridine hydrobromide (100 mg, 0.36 mmol)in ethanol (2 mL) was treated with 1-benzyl-2-thiourea (90 mg, 0.54mmol). The resulting yellow solution was concentrated, and the cruderesidue was purified on reverse phase HPLC to produceN-benzyl-4-(pyridin-2-yl)thiazol-2-amine.

A solution of N-benzyl-4-(pyridin-2-yl)thiazol-2-amine (60 mg, 0.23mmol) in DMF (2 mL) was cooled to 0° C. and treated withN-chlorosuccinimide (33 mg, 0.25 mmol), and the reaction mixture wasallowed to warm to room temperature. The solvent was evaporated, and theproduct was purified on reverse phase HPLC to produceN-benzyl-5-chloro-4-(pyridin-2-yl)thiazol-2-amine. MS (Q1) 302.2 (M)⁺.

Example 51 4-chloro-N-(3,5-dimethoxyphenyl)-3-(pyridin-2-yl)benzamide

A solution of 3-bromo-4-chlorobenzoic acid (250 mg, 1.1 mmol) in DMF (2mL) was treated with PyBop (550 mg, 1.1 mmol) and DIPEA (370 uL, 2.1mmol). After stirring the reaction mixture for 5 min. 3,5-dimethoxyanaline (105 mg, 0.69 mmol) was added and the reaction was stirred for16 h. The reaction mixture was diluted with ethyl acetate and washedwith 0.1 N HCl, 0.1 N sodium hydroxide and Brine, successively. Theorganic layer was dried (MgSO₄) and concentrated, and crude3-bromo-4-chloro-N-(3,5-dimethoxyphenyl)benzamide was used withoutfurther purification.

3-bromo-4-chloro-N-(3,5-dimethoxyphenyl)benzamide was dissolved in 0.5 M2-pyridylzincbromide (2.5 mL) and treated with Pd(PPh)₃)₄ (20 mg, 0.02mmol). The reaction mixture was heated to 155° C. in a sealed tube for20 min. in a microwave reactor. The resultant solution was diluted withEthyl acetate and washed with 0.1 N sodium hydroxide and then brine. Theorganic layer was dried (MgSO₄) and concentrated, and the crude residuewas partially purified by silica gel chromatography. Pure4-chloro-N-(3,5-dimethoxyphenyl)-3-(pyridin-2-yl)benzamide was obtainedby a second purification on reverse phase HPLC. MS (Q1) 369.1 (M)⁺.

Example 52N-(3-(3,5-bis(trifluoromethyl)phenyl)propyl)-4-chloro-3-(pyridin-2-yl)benzenamine

A solution of 3,5-bis(trifluoromethyl)hydrocinnamic acid (1.0 g, 3.5mmol) and TEA (0.46 g, 4.5 mmol) in THF (16 mL) was cooled to −40° C.(ethanol-water/dry ice bath). To this mixture was dropwise addedisobutyl chloroformate (0.56 g, 4.1 mmol) and stirring was continued foranother 1.5 hours while the temperature of the cooling bath wasmaintained between −40° C. and −20° C. Solid NaBH₄ (0.53 g, 14 mmol) wasadded, followed by H₂O (1.3 mL). The cloudy mixture was stirredovernight while warming to room temperature. After concentrating invacuo, the residue was partitioned between ethyl acetate and water. Theaqueous layer was acidified to pH 1 with 37% HCl and extracted withethyl acetate. The combined organic layers were washed sequentially withsaturated NaHCO₃, and brine, then dried (MgSO₄) and concentrated. Theresulting oil was purified by flash silica gel chromatography (6:4 ethylether-hexane) to yield 3-[3′,5′-bis(trifluoromethyl)phenyl]-1-propanol.

3-[3′,5′-bis(trifluoromethyl)phenyl]-1-propanol (0.88 g, 3.2 mmol) andCBr₄ (1.3 g, 4.0 mmol) were dissolved in CH₂Cl₂ (5 mL) and cooled to 0°C. Triphenylphosphine (1.3 g, 4.8 mmol) was added in three portions over0.5 h. The mixture was stirred at 0° C. for 10 min., then diluted withpentane (30 mL) and sat. NaHCO₃ (30 mL). The aqueous layer was separatedand washed with ethyl ether, and the combined organic layers were dried(MgSO₄) and concentrated. The residue was purified by silica gel flashchromatography (99:1 ethyl ether-hexane) to yield 0.8 g, (74%) of the3-[3′,5′-bis(trifluoromethyl)phenyl]-1-bromopropane.

4-chloro-3-(2′-pyridyl)aniline (10 mg, 0.05 mmol),3-[3′,5′-bis(trifluoromethyl)phenyl]-1-bromopropane (34 mg, 0.1 mmol)and K₂CO₃ (14 mg, 0.1 mmol) in DMF (1 mL) was stirred at 100° C.overnight. The reaction mixture was acidified with 1N HCl (aq.) andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried (MgSO₄) and concentrated. The crude was purified bypreparative HPLC to yieldN-(3-(3,5-bis(trifluoromethyl)phenyl)propyl)-4-chloro-3-(pyridin-2-yl)benzenamine.

Example 53N-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide

N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide(˜0.5 mmol) was used in Procedure A with5-trifluoromethyl-2-bromopyridine (113 mg, 0.5 mmol). Purified by silicagel chromatography (5-50% ethyl acetate/hexanes) to yieldN-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamideas a white foam: TLC R_(f)=0.30 (15% ethyl acetate/hexanes); MS (Q1) 460(M)⁺.

Example 54N-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(methylsulfonyl)benzamide(˜1.0 mmol) was used in Procedure A with5-trifluoromethyl-2-bromopyridine (226 mg, 1 mmol). Purified by silicagel chromatography (0-10% acetone/dichloromethane) to yieldN-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamideas a white solid: MS (Q1) 455 (M)⁺.

Example 55N-(4-chloro-3-(5-chloropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide

5-chloropyridin-2-yl trifluoromethanesulfonate (4.12 mmol) was used inProcedure I with trimethyltin chloride to yield5-chloro-2-(trimethylstannyl)pyridine. The crude material (˜4 mmol) wasused in Procedure K withN-(4-chloro-3-iodophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (2mmol). Purified by silica gel chromatography (0-50% ethylacetate/hexane) to yieldN-(4-chloro-3-(5-chloropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamideas a white solid: TLC R_(f)=0.48 (25% ethyl acetate/hexanes); MS (Q1)427 (M)⁺.

Example 56N-(4-chloro-3-(6-chloropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide

6-chloropyridin-2-yl trifluoromethanesulfonate (4.12 mmol) was used inProcedure I with trimethyltin chloride to yield2-chloro-6-(trimethylstannyl)pyridine. The crude material (˜4 mmol) wasused in Procedure K withN-(4-chloro-3-iodophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (2mmol). Purified by silica gel chromatography (5-45% ethylacetate/hexane) to yieldN-(4-chloro-3-(6-chloropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamideas a white solid: TLC R_(f)=0.45 (25% ethyl acetate/hexanes); MS (Q1)426 (M)⁺.

Example 57N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide

3-(triisopropylsilyloxy)pyridine (2.66 mmol) was used in Procedure Jwith hexamethyldistannane to yield5-(triisopropylsilyloxy)-2-(trimethylstannyl)pyridine. The crudematerial (˜0.55 mmol) was used in Procedure K withN-(4-chloro-3-iodophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.17mmol). Purified by silica gel chromatography (0-40% ethylacetate/hexane) to yieldN-(4-chloro-3-(5-(triisopropylsilyloxy)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamideas a yellow oil.N-(4-chloro-3-(5-(triisopropylsilyloxy)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide(1 mmol) was treated with TBAF (2 mL, 1 M in THF) in THF (1 mL) at 23°C. for thirty minutes, concentrated, redissolved in ethyl acetate,washed with brine, dried (MgSO₄), and concentrated. The crude solid waspurified by silica gel chromatography (0-10%isopropanol/dichloromethane) to yieldN-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamideas a white solid: TLC R_(f)=0.59 (10% ethyl acetate/hexanes); MS (Q1)408 (M)⁺.

Example 58N-(4-chloro-3-(5-methoxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide

N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide(0.12 mmol) was used in Procedure L with excess iodomethane. Purified bysilica gel chromatography (0-100% ethyl acetate/hexane) to yieldN-(4-chloro-3-(5-methoxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamideas a white solid: TLC R_(f)=0.57 (50% ethyl acetate/hexanes); MS (Q1)423 (M)⁺.

Example 59N-(4-chloro-3-(5-ethoxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide

N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide(0.05 mmol) was used in Procedure L with excess iodoethane. Purified bysilica gel chromatography (0-100% ethyl acetate/hexane) to yieldN-(4-chloro-3-(5-ethoxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamideas a white solid: TLC R_(f)=0.64 (50% ethyl acetate/hexanes); MS (Q1)436 (M)⁺.

Example 60N-(4-chloro-3-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide

N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide(0.12 mmol) was used in Procedure L with excess trifluoroethyl iodide.Purified by silica gel chromatography (0-40% ethyl acetate/hexane) toyieldN-(4-chloro-3-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamideas a white solid: TLC R_(f)=0.64 (40% ethyl acetate/hexanes); MS (Q1)490 (M)⁺.

Example 61N-(4-chloro-3-(4-ethylpyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide

N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide(˜1 mmol) was used in Procedure A with 4-ethyl-2-bromopyridine (1 mmol).Purified by silica gel chromatography (0-60% ethyl acetate/hexanes) toyieldN-(4-chloro-3-(4-ethylpyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamideas a tan solid: MS (Q1) 419 (M)⁺.

Example 62N-(4-chloro-3-(5-fluoropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide

N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide(˜1 mmol) was used in Procedure A with 5-fluoro-2-bromopyridine (1mmol). Purified by silica gel chromatography (5-45% ethylacetate/hexanes) to yieldN-(4-chloro-3-(5-fluoropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamideas a tan solid: MS (Q1) 409 (M)⁺.

Example 63N-(4-chloro-3-(5-phenylpyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide

5-phenylpyridin-2-yl trifluoromethanesulfonate (1.5 mmol) was used inProcedure J with trimethyltin chloride to yield5-phenyl-2-(trimethylstannyl)pyridine. The crude material (˜1.25 mmol)was used in Procedure K withN-(4-chloro-3-iodophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (1mmol). Purified by silica gel chromatography (1% acetone/methylenechloride) to yieldN-(4-chloro-3-(5-phenylpyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamideasa tan solid: TLC R_(f)=0.15 (1% acetone/methylene chloride); MS (Q1) 467(M)⁺.

Example 64(S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-methylpiperazin-1-yl)nicotinamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) and75 mg of (S)-2-methylpiperazine in 0.75 mL of butanol at 160° C. for 60min. Purification by reverse phase HPLC yielded(S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-methylpiperazin-1-yl)nicotinamide.MS (Q1) 408 (M)⁺.

Example 65(R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-methylpiperazin-1-yl)nicotinamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) and75 mg of (R)-2-methylpiperazine in 0.75 mL of butanol at 160° C. for 60min. Purification by reverse phase HPLC yielded(R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-methylpiperazin-1-yl)nicotinamide.MS (Q1) 408 (M)⁺.

Example 66N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)nicotinamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (75 mg) and114 mg of 2,6-dimethylpiperazine in 1 mL of butanol at 160° C. for 60min. Purification by reverse phase HPLC yieldedN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)nicotinamide.MS (Q1) 422.1 (M)⁺.

Example 67N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-3-yl)terephthalamide

320 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 400 mg of4-(methoxycarbonyl)benzoic acid via Procedure G to give methyl4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate.4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate was then hydrolyzedvia Procedure M to give 550 mg of4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid. 50 mg of4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to3-aminopyridine via Procedure G. The organic layer was evaporated todryness and purified on reverse phase HPLC to yieldN¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-3-yl)terephthalamide.MS (Q1) 429 (M)⁺.

Example 68N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(6-methoxypyridin-3-yl)terephthalamide

50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid wascoupled to 2-methoxy-5-aminopyridine via Procedure G. The product waspurified on reverse phase HPLC to yieldN¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(6-methoxypyridin-3-yl)terephthalamide.MS (Q1) 459 (M)⁺.

Example 69N¹-(6-aminopyridin-3-yl)-N⁴-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide

50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid wascoupled to 2,5-diaminopyridine via Procedure G. The product was purifiedon reverse phase HPLC to yieldN¹-(6-aminopyridin-3-yl)-N⁴-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide.MS (Q1) 444 (M)⁺.

Example 70N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-2-ylmethyl)terephthalamide

50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid wascoupled to 2-(aminomethyl)pyridine via Procedure G. The product waspurified on reverse phase HPLC to yieldN¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-2-ylmethyl)terephthalamide.MS (Q1) 443 (M)⁺.

Example 71N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-isopropylterephthalamide

50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid wascoupled to isopropylamine via Procedure G. The product was purified onreverse phase HPLC to yieldN¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-isopropylterephthalamide. MS(Q1) 394 (M)⁺.

Example 72N¹-tert-butyl-N⁴-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide

50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid wascoupled to tert-butylamine via Procedure G. The product was purified onreverse phase HPLC to yieldN¹-tert-butyl-N⁴-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS(Q1) 408 (M)⁺.

Example 73N⁴-tert-butyl-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide

67 mL of 2-chloro-1,4-dimethylbenzene and 356 g of PotassiumPermanganate were refluxed in 1.5 L of H₂O for several hours andmonitored for disappearance of starting material by TLC. The PotassiumPermanganate was filtered and the reaction mixture was acidified andfiltered to yield 2-chloroterephthalic acid. 46.8 g of2-chloroterephthalic acid was treated with a saturated HCl gas solutionin MeOH overnight at room temperature. The reaction mixture wasconcentrated, subjected to basic workup and dried to yield the dimethyl2-chloroterephthalate. 20 g of dimethyl 2-chloroterephthalate was cooledto 0° C. in DCM and 87 mL of a 1M in DCM solution of BBr₃ was addeddropwise over several hours. The reaction mixture was subsequentlywarmed to room temperature and stirred until complete. Following basicworkup, 2-chloro-4-(methoxycarbonyl)benzoic acid was purified by ISCOCombi-Flash. 959 mg of 2-chloro-4-(methoxycarbonyl)benzoic acid wascoupled to 750 mg of 4-chloro-3-(pyridin-2-yl)aniline via procedure G. 1g of methyl3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate washydrolyzed via Procedure M to give3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid. 50 mgof 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid wascoupled to tert-butylamine via Procedure G. The product was purified onreverse phase HPLC to yieldN⁴-tert-butyl-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide.MS (Q1) 443.2 (M)⁺.

Example 742-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)benzamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to N-(2-hydroxyethyl)piperazine via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)benzamide.MS (Q1) 499 (M)⁺.

Example 752-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-methylpiperazine-1-carbonyl)benzamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 1-methylpiperazine via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-methylpiperazine-1-carbonyl)benzamide.MS (Q1) 469 (M)⁺.

Example 764-(4-acetylpiperazine-1-carbonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 1-acetylpiperazine via Procedure G. The product waspurified on reverse phase HPLC to yield4-(4-acetylpiperazine-1-carbonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 497 (M)⁺.

Example 772-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-(methylsulfonyl)piperazine-1-carbonyl)benzamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 1-sulfonylpiperazine via Procedure G. The productwas purified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-(methylsulfonyl)piperazine-1-carbonyl)benzamide.MS (Q1) 533 (M)⁺.

Example 782-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(morpholine-4-carbonyl)benzamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to morpholine via Procedure G. The product was purifiedon reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(morpholine-4-carbonyl)benzamide.MS (Q1) 456 (M)⁺.

Example 792-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3,5-dimethylpiperazine-1-carbonyl)benzamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 2,6-dimethylpiperazine via Procedure G. The productwas purified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3,5-dimethylpiperazine-1-carbonyl)benzamide.MS (Q1) 483 (M)⁺.

Example 802-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-3-ylmethyl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 3-(aminomethyl)pyridine via Procedure G. The productwas purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-3-ylmethyl)terephthalamide.MS (Q1) 477 (M)⁺.

Example 812-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-2-ylmethyl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 2-(aminomethyl)pyridine via Procedure G. The productwas purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-2-ylmethyl)terephthalamide.MS (Q1) 477 (M)⁺.

Example 822-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-4-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 4-aminopyridine via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-4-yl)terephthalamide.MS (Q1) 463 (M)⁺.

Example 832-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-3-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 3-aminopyridine via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-3-yl)terephthalamide.MS (Q1) 463 (M)⁺.

Example 842-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiomorpholine-4-carbonyl)benzamide(S-oxidized thiomorpholine)

100 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to thiomorpholine via Procedure G. Crude2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiomorpholine-4-carbonyl)benzamidewas reacted via Procedure R to oxidize the thiomorpholine sulfur andpurified via reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiomorpholine-4-carbonyl)benzamide(in which the thiomorpholline sulfur is oxidized to SO₂). MS (Q1) 504(M)⁺.

Example 852-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiazolidine-3-carbonyl)benzamide(S-oxidized thiazolidine)

100 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to thiazolidine via Procedure G. Crude2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiazolidine-3-carbonyl)benzamidewas reacted via Procedure R and purified via reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiazolidine-3-carbonyl)benzamide(in which the thiazolidine sulfur is oxidized to SO₂). MS (Q1) 490 (M)⁺.

Example 862-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1-methyl-1H-pyrazol-5-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 5-amino-1-methylpyrazole via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1-methyl-1H-pyrazol-5-yl)terephthalamide.MS (Q1) 466 (M)⁺.

Example 872-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(isoxazol-5-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 5-aminoisoxazole via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(isoxazol-5-yl)terephthalamide.MS (Q1) 463 (M)⁺.

Example 882-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(4,5-dihydrothiazol-2-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 2-amino-4,5-dihydrothiazole via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(4,5-dihydrothiazol-2-yl)terephthalamide.MS (Q1) 471 (M)⁺.

Example 892-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1H-imidazol-2-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 2-aminoimidazole via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1H-imidazol-2-yl)terephthalamide.MS (Q1) 452 (M)⁺.

Example 902-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(4H-1,2,4-triazol-4-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 4-amino-1,2,4-triazole via Procedure G. The productwas purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(4H-1,2,4-triazol-4-yl)terephthalamide.MS (Q1) 453 (M)⁺.

Example 912-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(thiazol-2-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 2-aminothiazole via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(thiazol-2-yl)terephthalamide.MS (Q1) 469 (M)⁺.

Example 922-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1H-1,2,4-triazol-5-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 3-amino-1,2,4-triazole via Procedure G. The productwas purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(H-1,2,4-triazol-5-yl)terephthalamide.MS (Q1) 453 (M)⁺.

Example 932-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiazolidine-3-carbonyl)benzamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to thiazoline via Procedure G. The product was purifiedon reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiazolidine-3-carbonyl)benzamide.MS (Q1) 459 (M)⁺.

Example 942-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(4,5-dihydrooxazol-2-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 2-amino-4,5-dihydrooxazole via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(4,5-dihydrooxazol-2-yl)terephthalamide.MS (Q1) 456 (M)⁺.

Example 952-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1,4,5,6-tetrahydropyrimidine-1-carbonyl)benzamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 1,4,5,6-tetrahydropyrimidine via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1,4,5,6-tetrahydropyrimidine-1-carbonyl)benzamide.MS (Q1) 454 (M)⁺.

Example 962-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-oxopiperazine-1-carbonyl)benzamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 3-oxopiperazine via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-oxopiperazine-1-carbonyl)benzamide.MS (Q1) 470 (M)⁺.

Example 972-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-methoxyterephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to N-methylhydroxylamine hydrochloride via Procedure G.The product was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-methoxyterephthalamide.MS (Q1) 417 (M)⁺.

Example 982-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-hydroxyterephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to hydroxylamine hydrochloride via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-hydroxyterephthalamide.MS (Q1) 403 (M)⁺.

Example 992-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyrrolidine-1-carbonyl)benzamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to pyrolidine via Procedure G. The product was purifiedon reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyrrolidine-1-carbonyl)benzamide.MS (Q1) 441 (M)⁺.

Example 100N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonylmethyl)benzamide

Ethanesulfonyl chloride was reduced to sodium ethanesulfinate accordingto the procedure in J. Med. Chem. 1989, vol. 32, no. 11, p2436. Briefly,2.5 ml of ethanesulfonyl chloride was added dropwise to a solution of3.67 g of sodium carbonate and 5.51 g of sodium sulfate in 13 mL ofwater. After completion of the reaction the water was evaporated and thesolids were suspended in ethanol and heated to 80° C. for 1 h prior tofiltering the solids. The filtrate was then evaporated to give 2.5 gramsof the sodium ethanesulfinate. 293 mg of the sodium ethansulfinate wascombined with 230 mg of methyl (4-bromoethyl)benzoate in 2 mL of DMF andheated to 120 C for 5 min in a microwave reactor. The reaction was thenextracted with Ethyl Acetate and Brine to give 250 mg of methyl4-(ethylsulfonylmethyl)benzoate after evaporation of the organic layer.200 mg of methyl 4-(ethylsulfonylmethyl)benzoate was hydrolyzed viaProcedure M to give 119 mg of 4-(ethylsulfonylmethyl)benzoic acid.

50 mg of 4-(ethylsulfonylmethyl)benzoic acid was coupled with 67 mg of4-chloro-3-(pyridin-2-yl)aniline via Procedure G. This product wasrecrystallized from methanol to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonylmethyl)benzamide. MS(Q1) 415 (M)⁺.

Example 101N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonylmethyl)benzamide

N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonylmethyl)benzamidewas prepared using the same procedure asN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonylmethyl)benzamideexcept propane-2-sulfonyl chloride was substituted for ethanesulfonylchloride. The product was purified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonylmethyl)benzamide.MS (Q1) 429 (M)⁺.

Example 1022-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-ethylterephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to ethylamine via Procedure G. The product was purifiedon reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-ethylterephthalamide.MS (Q1) 415 (M)⁺.

Example 103(S)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-((tetrahydrofuran-2-yl)methyl)terephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to (S)-(+)-tetrahydrofurylamine via Procedure G. Theproduct was purified on reverse phase HPLC to yield(S)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-((tetrahydrofuran-2-yl)methyl)terephthalamide.MS (Q1) 471 (M)⁺.

Example 1042-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(3-methoxypropyl)terephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 3-methoxypropylamine via Procedure G. The productwas purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(3-methoxypropyl)terephthalamide.MS (Q1) 459 (M)⁺.

Example 1052-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(3-hydroxypropyl)terephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 3-hydroxypropylamine via Procedure G. The productwas purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(3-hydroxypropyl)terephthalamide.MS (Q1) 445 (M)⁺.

Example 106(S)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1-hydroxypropan-2-yl)terephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to (S)-2-amino-1-propanol via Procedure G. The productwas purified on reverse phase HPLC to yield(S)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1-hydroxypropan-2-yl)terephthalamide.MS (Q1) 445 (M)⁺.

Example 107(S)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1-methoxypropan-2-yl)terephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to (S)-1-methoxy-2-propylamine via Procedure G. Theproduct was purified on reverse phase HPLC to yield(S)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1-methoxypropan-2-yl)terephthalamide.MS (Q1) 459 (M)⁺.

Example 108N⁴-(3-(1H-imidazol-1-yl)propyl)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 1-(3-aminopropyl)imidazole via Procedure G. Theproduct was purified on reverse phase HPLC to yieldN⁴-(3-(1H-imidazol-1-yl)propyl)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide.MS (Q1) 495 (M)⁺.

Example 109N⁴-(2-(1H-imidazol-4-yl)ethyl)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to hystamine via Procedure G. The product was purifiedon reverse phase HPLC to yieldN⁴-(2-(1H-imidazol-4-yl)ethyl)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide.MS (Q1) 481 (M)⁺.

Example 1102-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-methylterephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to methylamine hydrochloride via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-methylterephthalamide.MS (Q1) 401 (M)⁺.

Example 1112-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-diethylterephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to diethylamine hydrochloride via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴,N⁴-diethylterephthalamide.MS (Q1) 443 (M)⁺.

Example 112(S)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-hydroxypropyl)-terephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to (S)-1-amino-2-propanol via Procedure G. The productwas purified on reverse phase HPLC to yield(S)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-hydroxypropyl)terephthalamide.MS (Q1) 444 (M)⁺.

Example 1132-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-methoxyethyl)terephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 2-methoxyethanamine via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-methoxyethyl)terephthalamide.MS (Q1) 444 (M)⁺.

Example 1142-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1-methylpiperidin-4-yl)terephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 4-amino-1-methylpiperidine via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1-methylpiperidin-4-yl)terephthalamide.MS (Q1) 483 (M)⁺.

Example 1152-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(3-(diethylamino)propyl)terephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to N,N-diethylpropylenediamine via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(3-(diethylamino)propyl)terephthalamide.MS (Q1) 499 (M)⁺.

Example 1162-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-(pyrrolidin-1-yl)ethyl)terephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to N-(2-aminoethyl)pyrrolidine via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-(pyrrolidin-1-yl)ethyl)terephthalamide.MS (Q1) 483 (M)⁺.

Example 117N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-trimethylterephthalamide

In a sealed tube, 1.94 g of dimethyl 2-bromoterephthalate was dissolvedin 4 mL of HMPA and degassed with nitrogen prior to adding 1.1 mL oftetramethyl tin and 0.077 g of palladium tetrakistriphenylphosphene.After sealing the tube, the reaction was heated to 65° C. for 16 h. Thereaction was then partitioned into ethylether and water and extracted.The organic layers were washed with 5% ammonium hydroxide, 1N HCl, againwith 5% ammonium hydroxide, and finally with water. Filtration of thesolvent through sodium sulfate and evaporation gave 1.44 g of crudedimethyl 2-methylterephthalate. 210 mg of dimethyl 2-methylterephthalatewas hydrolyzed via Procedure M to give4-(methoxycarbonyl)-3-methylbenzoic acid. Silica gel chromatography wasperformed (0% to 70% EtOAc gradient in Hexanes) to yield 115 mg of4-(methoxycarbonyl)-3-methylbenzoic acid.4-(methoxycarbonyl)-3-methylbenzoic acid was then coupled todimethylamine hydrochloride via Procedure G. The crude methyl4-(dimethylcarbamoyl)-2-methylbenzoate was then hydrolyzed via ProcedureM to give 110 mg of 4-(dimethylcarbamoyl)-2-methylbenzoic acid.4-chloro-3-(pyridin-2-yl)aniline was coupled to 110 mg of4-(dimethylcarbamoyl)-2-methylbenzoic acid via Procedure G to yieldN¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴,N⁴,2-trimethylterephthalamide.MS (Q1) 394 (M)⁺.

Example 1182-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-propylterephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to propylamine via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-propylterephthalamide.MS (Q1) 430 (M)⁺.

Example 1192-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-hydroxyethyl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to propanolamine via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-hydroxyethyl)terephthalamide.MS (Q1) 428 (M)⁺.

Example 120 2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to ammonium chloride via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1)386 (M)⁺.

Example 121N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1H-tetrazol-1-yl)benzamide

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg)and 4-(1H-tetrazol-1-yl)benzoic acid to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1H-tetrazol-1-yl)benzamide. MS(Q1) 421.0 (M)⁺.

Example 1222-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-ethylpiperazine-1-carbonyl)benzamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 1-ethylpiperazine via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-ethylpiperazine-1-carbonyl)benzamide.MS (Q1) 483 (M)⁺.

Example 1232-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(piperazine-1-carbonyl)benzamide

50 mg 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acidwas coupled to Boc-piperazine via Procedure G. The organic layer wasevaporated to dryness and treated with TFA. After 1 h the TFA wasremoved and the crude was purified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(piperazine-1-carbonyl)benzamide.MS (Q1) 455 (M)⁺.

Example 1242-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2,2,2-trifluoroethyl)terephthalamide

75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 2,2,2-trifluoroethylamine via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2,2,2-trifluoroethyl)terephthalamide.MS (Q1) 469 (M)⁺.

Example 1256-(2-(1H-imidazol-5-yl)ethylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) and100 mg of hystamine in butanol (0.5 mL). The crude reaction was purifiedby reverse phase HPLC to yield6-(2-(1H-imidazol-5-yl)ethylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide.MS (Q1) 419 (M)⁺.

Example 1266-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) and0.12 mL of acetylpiperazine in butanol (0.5 mL). The crude reaction waspurified by reverse phase HPLC to yield6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide.MS (Q1) 436 (M)⁺.

Example 1276-(3-(1H-imidazol-1-yl)propylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) and125 mg of 1-(3-aminopropyl)imidazole in butanol (0.5 mL). The crudereaction was purified by reverse phase HPLC to yield6-(3-(1H-imidazol-1-yl)propylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide.MS (Q1) 433 (M)⁺.

Example 128N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-(2-oxopyrrolidin-1-yl)propylamino)nicotinamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) and0.42 mL of 1-(3-aminopropyl)-2-pyrrolidinone in butanol (0.5 mL). Thecrude reaction was purified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-(2-oxopyrrolidin-1-yl)propylamino)nicotinamide.MS (Q1) 450 (M)⁺.

Example 129N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-morpholinopropylamino)nicotinamide

Procedure F was performed usingN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) and0.14 mL of N-(3-aminopropyl)morpholine in butanol (0.5 mL). The crudereaction was purified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-morpholinopropylamino)nicotinamide.MS (Q1) 452 (M)⁺.

Example 130N-(4-chloro-3-(pyridin-2-yl)phenyl)benzo[d][1,2,3]thiadiazole-5-carboxamide

50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled tobenzo-1,2,3-thiadiazole-5-carboxylic acid via Procedure G. The crudeproduct was purified via reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)benzo[d][1,2,3]thiadiazole-5-carboxamide.MS (Q1) 367 (M)⁺.

Example 1312-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)terephthalamide

60 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol viaProcedure G. The crude product was purified on reverse phase HPLC toyield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)terephthalamide.MS (Q1) 518.2 (M)⁺.

Example 1322-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)terephthalamide

60 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol viaProcedure G. The crude product was purified on reverse phase HPLC toyield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)terephthalamide.MS (Q1) 518.2 (M)⁺.

Example 133N⁴-benzyl-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-hydroxyethyl)-terephthalamide

40 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 2-(benzylamino)ethanol via Procedure G. The crudeproduct was purified on reverse phase HPLC to yieldN⁴-benzyl-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-hydroxyethyl)terephthalamide.MS (Q1) 520 (M)⁺.

Example 1342-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-methyl-N⁴-(pyridin-2-ylmethyl)terephthalamide

40 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to N-methyl-1-(pyridin-2-yl)methanamine via ProcedureG. The crude product was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-methyl-N⁴-(pyridin-2-ylmethyl)terephthalamide.MS (Q1) 491 (M)⁺.

Example 135N⁴-benzyl-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-methylterephthalamide

40 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to N-methyl-1-phenylmethanamine via Procedure G. Thecrude product was purified on reverse phase HPLC to yieldN⁴-benzyl-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-methylterephthalamide.MS (Q1) 490.1 (M)⁺.

Example 136N⁴-(2-aminobenzyl)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide

60 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to N¹-phenylethane-1,2-diamine via Procedure G. Thecrude product was purified on reverse phase HPLC to yieldN⁴-(2-aminobenzyl)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide.MS (Q1) 491 (M)⁺.

Example 137N⁴-benzyl-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide

60 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to benzylamine via Procedure G. The crude product waspurified on reverse phase HPLC to yieldN⁴-benzyl-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide.MS (Q1) 476 (M)⁺.

Example 138(R)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-hydroxy-1-phenylethyl)terephthalamide

60 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to (R)-2-amino-2-phenylethanol via Procedure G. Thecrude product was purified on reverse phase HPLC to yield(R)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-hydroxy-1-phenylethyl)terephthalamide.MS (Q1) 506 (M)⁺.

Example 139N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-methyl-1,4-diazepan-1-yl)nicotinamide

50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide wasreacted with 1-methyl-1,4-diazepane via Procedure F. The reaction wasevaporated to dryness and purified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-methyl-1,4-diazepan-1-yl)nicotinamide.MS (Q1) 422 (M)⁺.

Example 140N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(1,4-diazepan-1-yl)nicotinamide

50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide wasreacted with 1,4-diazepane via Procedure F. The reaction was evaporatedto dryness and purified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(1,4-diazepan-1-yl)nicotinamide.MS (Q1) 408 (M)⁺.

Example 1412-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-(phenylamino)ethyl)terephthalamide

62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to N¹-phenylethane-1,2-diamine via Procedure G. Thecrude product was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-(phenylamino)ethyl)terephthalamide.MS (Q1) 505.1 (M)⁺.

Example 142(S)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-hydroxy-1-phenylethyl)terephthalamide

62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to (S)-2-amino-2-phenylethanol via Procedure G. Thecrude product was purified on reverse phase HPLC to yield(S)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-hydroxy-1-phenylethyl)terephthalamide.MS (Q1) 506 (M)⁺.

Example 1432-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1-phenylethyl)terephthalamide

62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 1-phenylethanamine via Procedure G. The crudeproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1-phenylethyl)terephthalamide.MS (Q1) 490.1 (M)⁺.

Example 1442-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(4-(methylsulfonyl)benzyl)-terephthalamide

62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to (4-(methylsulfonyl)phenyl)methanamine via ProcedureG. The crude product was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(4-(methylsulfonyl)benzyl)terephthalamide.MS (Q1) 554 (M)⁺.

Example 145N-(3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide

75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to4-((tert-butoxycarbonylamino)methyl)-2-chlorobenzoic acid via ProcedureG to yield tert-butyl3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate.Tert-butyl3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate wassubsequently treated with 4N HCl in Dioxane to remove the Boc protectinggroup and form the HCl salt of4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.54 mg of the crude HCl salt of4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamidewas coupled to picolinic acid via Procedure G. The crude product waspurified by reverse phase HPLC to yieldN-(3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide.MS (Q1) 477.3 (M)⁺.

Example 146N-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide

75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to4-((tert-butoxycarbonylamino)methyl)benzoic acid via Procedure G toyield tert-butyl4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate. Tert-butyl4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate wassubsequently treated with 4N HCl in Dioxane to remove the Boc protectinggroup and form the HCl salt of4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 50 mg ofthe crude HCl salt of4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupledto picolinic acid via Procedure G. The crude product was purified byreverse phase HPLC to yieldN-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide. MS(Q1) 443.3 (M)⁺.

Example 147N⁵-(4-chloro-3-(pyridin-2-yl)phenyl)-N²-isopropylpyridine-2,5-dicarboxamide

250 mg of 5-(methoxycarbonyl)picolinic acid was coupled toisopropylamine via Procedure G. Crude methyl6-(isopropylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield227 mg of 6-(isopropylcarbamoyl)nicotinic acid. 60 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to6-(isopropylcarbamoyl)nicotinic acid via Procedure G. The crude productwas purified by reverse phase HPLC to yieldN⁵-(4-chloro-3-(pyridin-2-yl)phenyl)-N²-isopropylpyridine-2,5-dicarboxamide.MS (Q1) 395.1 (M)⁺.

Example 148N²-tert-butyl-N⁵-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide

250 mg of 5-(methoxycarbonyl)picolinic acid was coupled totert-butylamine via Procedure G. Crude methyl6-(tert-butylcarbamoyl)nicotinate was hydrolyzed via Procedure M toyield 250 mg of 6-(tert-butylcarbamoyl)nicotinic acid. 60 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to6-(tert-butylcarbamoyl)nicotinic acid via Procedure G. The crude productwas purified by reverse phase HPLC to yieldN²-tert-butyl-N⁵-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide.MS (Q1) 409 (M)⁺.

Example 149N⁵-(4-chloro-3-(pyridin-2-yl)phenyl)-N²-(pyridin-2-ylmethyl)pyridine-2,5-dicarboxamide

250 mg of 5-(methoxycarbonyl)picolinic acid was coupled topyridin-2-ylmethanamine via Procedure G. Crude methyl6-(pyridin-2-ylmethylcarbamoyl)nicotinate was hydrolyzed via Procedure Mto yield 250 mg of 6-(pyridin-2-ylmethylcarbamoyl)nicotinic acid. 60 mgof 4-chloro-3-(pyridin-2-yl)aniline was coupled to6-(pyridin-2-ylmethylcarbamoyl)nicotinic acid via Procedure G. The crudeproduct was purified by reverse phase HPLC to yieldN⁵-(4-chloro-3-(pyridin-2-yl)phenyl)-N²-(pyridin-2-ylmethyl)pyridine-2,5-dicarboxamide.MS (Q1) 444.1 (M)⁺.

Example 150N²-benzyl-N⁵-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide

250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to benzylaminevia Procedure G. Crude methyl 6-(benzylcarbamoyl)nicotinate washydrolyzed via Procedure M to yield 300 mg of6-(benzylcarbamoyl)nicotinic acid. 60 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to6-(benzylcarbamoyl)nicotinic acid via Procedure G. The crude product waspurified by reverse phase HPLC to yieldN²-benzyl-N⁵-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide.MS (Q1) 443.1 (M)⁺.

Example 151N⁵-(4-chloro-3-(pyridin-2-yl)phenyl)-N²-(6-methoxypyridin-3-yl)pyridine-2,5-dicarboxamide

250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to6-methoxypyridin-3-amine via Procedure G. Crude methyl6-(6-methoxypyridin-3-ylcarbamoyl)nicotinate was hydrolyzed viaProcedure M to yield 196 mg of6-(6-methoxypyridin-3-ylcarbamoyl)nicotinic acid. 60 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to6-(6-methoxypyridin-3-ylcarbamoyl)nicotinic acid via Procedure G. Thecrude product was recrystallized to yield pureN⁵-(4-chloro-3-(pyridin-2-yl)phenyl)-N²-(6-methoxypyridin-3-yl)pyridine-2,5-dicarboxamide.MS (Q1) 460 (M)⁺.

Example 1522-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-((6-methylpyridin-2-yl)methyl)-terephthalamide

2.5 mL of Diisopropylazodicarboxylate in 1.5 mL of THF was addeddropwise to a solution of 250 mg of (6-methylpyridin-2-yl)methanol, 2.8g of Triphenylphosphine and 1.6 g of isoindoline-1,3-dione in anhydrousTHF at room temperature. The reaction was stirred for 2 hours andmonitored by TLC. Upon completion, the solvent was concentrated, thecrude material was extracted in water and Chloroform 3 times and driedover Magnesium Sulfate. The crude was purified via ISCO Combi-Flash toyield 2-((6-methylpyridin-2-yl)methyl)isoindoline-1,3-dione. 350 mg of2-((6-methylpyridin-2-yl)methyl)isoindoline-1,3-dione was treated with440 μL of Hydrazine Monohydrate in EtOH and refluxed for several hoursto yield (6-methylpyridin-2-yl)methanamine. The crude(6-methylpyridin-2-yl)methanamine was evaporated and directly coupled to50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid via Procedure G. The crude product was purified on reverse phaseHPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-((6-methylpyridin-2-yl)methyl)terephthalamide.MS (Q1) 491.1 (M)⁺.

Example 153N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-hydroxypropylsulfonyl)methyl)benzamide

1 g of methyl 4-(bromomethyl)benzoate was reacted with1-mercaptopropan-2-ol via Procedure Q. 1 g of methyl4-((2-hydroxypropylthio)methyl)benzoate was oxidized with 2 g of MCPBAin DCM at −78° C. to form crude methyl4-((2-hydroxypropylsulfonyl)methyl)benzoate. The reaction was evaporatedand purified by ISCO Combi-Flash to yield 567 mg of pure methyl4-((2-hydroxypropylsulfonyl)methyl)benzoate which was subsequentlyhydrolyzed via Procedure M to give 328 mg of4-((2-hydroxypropylsulfonyl)methyl)benzoic acid. 50 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-((2-hydroxypropylsulfonyl)methyl)benzoic acid via Procedure G. Thecrude product was purified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-hydroxypropylsulfonyl)methyl)benzamide.MS (Q1) 445.3 (M)⁺.

Example 154(R)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-hydroxypropyl)terephthalamide

100 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to (R)-2-amino-2-phenylethanol via Procedure G. Thecrude product was purified on reverse phase HPLC to yield(R)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-hydroxypropyl)terephthalamide.MS (Q1) 444.3 (M)⁺.

Example 155N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-(dimethylamino)ethylsulfonyl)methyl)-benzamide

500 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(bromomethyl)benzoic acid via Procedure E. 170 mg of4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reactedwith 2-(dimethylamino)ethanethiol hydrochloride via Procedure Q. 140 mgof crudeN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-(dimethylamino)ethylthio)methyl)benzamidewas reacted with oxone via Procedure R. The crude product was purifiedby reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-(dimethylamino)ethylsulfonyl)methyl)benzamide.MS (Q1) 458.3 (M)⁺.

Example 1562-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(6-methoxypyridin-3-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 6-methoxypyridin-3-amine via Procedure G. The crudeproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(6-methoxypyridin-3-yl)terephthalamide.MS (Q1) 493 (M)⁺.

Example 157N⁴-(6-aminopyridin-3-yl)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to pyridine-2,5-diamine via Procedure G. The crudeproduct was purified on reverse phase HPLC to yieldN⁴-(6-aminopyridin-3-yl)-2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide.MS (Q1) 478 (M)⁺.

Example 1582-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(6-chloropyridin-3-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 6-chloropyridin-3-amine via Procedure G. The crudeproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(6-chloropyridin-3-yl)terephthalamide.MS (Q1) 497 (M)⁺.

Example 1592-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-2-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to pyridin-2-amine via Procedure G. The crude productwas purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(pyridin-2-yl)terephthalamide.MS (Q1) 463 (M)⁺.

Example 1602-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(piperidin-4-ylmethyl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to piperidin-4-ylmethanamine via Procedure G. The crudeproduct was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(piperidin-4-ylmethyl)terephthalamide.MS (Q1) 483 (M)⁺.

Example 1612-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1,3-dimethyl-1H-pyrazol-5-yl)terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 1,3-dimethyl-1H-pyrazol-5-amine via Procedure G. Thecrude product was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(1,3-dimethyl-1H-pyrazol-5-yl)terephthalamide.MS (Q1) 480 (M)⁺.

Example 1622-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-(methylsulfonyl)ethyl)-terephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to 2-(methylsulfonyl)ethanamine via Procedure G. Thecrude product was purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-(2-(methylsulfonyl)ethyl)terephthalamide.MS (Q1) 492 (M)⁺.

Example 1632-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-isopropylterephthalamide

50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoicacid was coupled to isopropylamine via Procedure G. The crude productwas purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴-isopropylterephthalamide.MS (Q1) 428 (M)⁺.

Example 1642-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methyl-sulfonamido)benzamide

To 5 g of methyl 2-chloro-4-nitrobenzoate in 100 mL of EtOH was added 20g of Tin (II) Chloride in portions. The reaction was heated to 55° C.and monitored by TLC until complete. Solvent was concentrated andextraction was performed in Ethyl Acetate and water with TEA to reduceemulsions. The organic layer was dried over Magnesium Sulfate, filteredand concentrated to give 3.9 g of methyl 4-amino-2-chlorobenzoate. 1 gof methyl 4-amino-2-chlorobenzoate was cooled to 0° C. in DCM with 485μL of Pyridine before Methanesulfonyl Chloride was added dropwise. Thereaction was allowed to warm to room temperature and stir overnight.Solvent was concentrated and the crude material was dissolved in EthylAcetate and extracted with saturated bicarbonate solution and thenbrine. The crude material was dried over Magnesium Sulfate, filtered andconcentrated to give 1.54 g of methyl2-chloro-4-(methylsulfonamido)benzoate. 107 μL of1-bromo-2-methoxyethane and 556 mg of Cesium Carbonate were added to 150mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in DMF and stirredat room temperature for 16 hours. The reaction mixture was extracted inEthyl Acetate twice with saturated bicarbonate and once with brine,dried over Magnesium Sulfate, filtered and concentrated to give methyl2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate. 182 mg ofmethyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate washydrolyzed via Procedure M to yield 169 mg of crude2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid. 65 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid viaProcedure G. The crude product was purified by reverse phase HPLC toyield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methylsulfonamido)benzamide.MS (Q1) 494 (M)⁺.

Example 1654-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

200 μL of 1-(2-bromoethyl)-1H-pyrrole and 556 mg of Cesium Carbonatewere added to 150 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate inDMF and stirred at room temperature for 16 hours. The reaction mixturewas extracted in Ethyl Acetate twice with saturated bicarbonate and oncewith brine, dried over Magnesium Sulfate, filtered and concentrated togive methyl4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chlorobenzoate. 230mg of methyl4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chlorobenzoate washydrolyzed via Procedure M to yield 221 mg of crude4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chlorobenzoic acid.

64 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chlorobenzoic acidvia Procedure G. The crude product was purified by reverse phase HPLC toyield4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 529 (M)⁺.

Example 1662-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-isobutylmethylsulfonamido)-benzamide

175 μL of 1-iodo-2-methylpropane and 740 mg of Cesium Carbonate wereadded to 200 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in 2 mLof DMF and stirred in the microwave at 140° C. for 30 minutes. Thereaction mixture was extracted in Ethyl Acetate twice with water, driedover Magnesium Sulfate, filtered, concentrated and purified on ISCOCombi-Flash to give methyl2-chloro-4-(N-isobutylmethylsulfonamido)benzoate. 120 mg of methyl2-chloro-4-(N-isobutylmethylsulfonamido)benzoate was hydrolyzed viaProcedure M to yield 110 mg of crude2-chloro-4-(N-isobutylmethylsulfonamido)benzoic acid. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to2-chloro-4-(N-isobutylmethylsulfonamido)benzoic acid via Procedure G.The crude product was purified by reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-isobutylmethylsulfonamido)benzamide.MS (Q1) 492 (M)⁺.

Example 1672-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-morpholinoethyl)methyl-sulfonamido)benzamide

1.2 g of 4-(2-chloroethyl)morpholine and 2.5 g of Cesium Carbonate wereadded to 334 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in 7 mLof DMF and stirred in the microwave at 150° C. for 30 minutes. Thereaction mixture was extracted in Ethyl Acetate twice with water, driedover Magnesium Sulfate, filtered, concentrated to give crude methyl2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoate. 476 mg ofmethyl 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoate washydrolyzed via Procedure M and purified by reverse phase HPLC to yield460 mg of crude2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoic acid. 100 mgof 4-chloro-3-(pyridin-2-yl)aniline was coupled to2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoic acid viaProcedure G. The crude product was purified by reverse phase HPLC toyield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-morpholinoethyl)methylsulfonamido)benzamide.MS (Q1) 549 (M)⁺.

Example 168N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonylmethyl)benzamide

410 mg of dimethyl 2-methylterephthalate was hydrolyzed via Procedure Mand purified by ISCO Combi-Flash to afford4-(methoxycarbonyl)-3-methylbenzoic acid. 255 mg of4-(methoxycarbonyl)-3-methylbenzoic acid was cooled to 0° C. in 2 mL ofTHF before a solution of 2.6 mL of 1M BH₃-THF complex in THF was addeddropwise. The ice bath was subsequently removed and the reaction wasstirred at room temperature until reaction stalled out at ˜50% completeby TLC. The reaction was re-cooled to 0° C. and another 2.6 mL ofBH₃-THF was added dropwise before the ice bath was removed. Uponcompletion, the reaction was re-cooled to 0° C. and quenched with 3N HCldropwise. The aqueous layer was extracted 2 times with Ethyl Acetate andthe organic layer was then extracted once with bicarbonate solution andbrine, dried over Magnesium Sulfate, filtered and concentrated to givemethyl 4-(hydroxymethyl)-2-methylbenzoate. 220 mg of methyl4-(hydroxymethyl)-2-methylbenzoate was cooled to 0° C. in 5 mL of DCMbefore adding 260 mg of Triphenylphosphine and 395 mg of NBS. Thereaction was concentrated and directly purified via ISCO Combi-Flash togive pure methyl 4-(bromomethyl)-2-methylbenzoate. 255 mg of methyl4-(bromomethyl)-2-methylbenzoate was reacted via Procedure O to givemethyl 2-methyl-4-(methylsulfonylmethyl)benzoate. 250 mg of methyl2-methyl-4-(methylsulfonylmethyl)benzoate was then hydrolyzed uponheating to 45° C. for 1 hour via Procedure M to give2-methyl-4-(methylsulfonylmethyl)benzoic acid. 202 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to2-methyl-4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crudeproduct was purified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonylmethyl)benzamide.MS (Q1) 415 (M)⁺.

Example 1692-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methylmethyl-sulfonamido)benzamide

78 μL of iodomethane and 447 mg of Cesium Carbonate were added to 300 mgof methyl 2-chloro-4-(methylsulfonamido)benzoate in 3 mL of DMF andstirred at room temperature for 16 hours. The reaction mixture wasextracted in Ethyl Acetate twice with saturated bicarbonate and oncewith brine, dried over Magnesium Sulfate, filtered and concentrated togive crude methyl 2-chloro-4-(N-methylmethylsulfonamido)benzoate. 295 mgof methyl 2-chloro-4-(N-methylmethylsulfonamido)benzoate was hydrolyzedvia Procedure M to yield 249 mg of2-chloro-4-(N-methylmethylsulfonamido)benzoic acid.

100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to2-chloro-4-(N-methylmethylsulfonamido)benzoic acid via Procedure G. Thecrude product was purified by reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methylmethylsulfonamido)benzamide.MS (Q1) 450 (M)⁺.

Example 170N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide

500 mg of methyl 4-(bromomethyl)benzoate was reacted with 480 mg oftert-butyl 3-oxopiperazine-1-carboxylate and 1 g of Cesium Carbonate in9 mL of DMF at 45° C. Upon completion, the reaction was extracted inEthyl Acetate 2 times saturated bicarbonate, dried over MagnesiumSulfate, filtered and concentrated to give tert-butyl4-(4-(methoxycarbonyl)benzyl)-3-oxopiperazine-1-carboxylate. 613 mg oftert-butyl 4-(4-(methoxycarbonyl)benzyl)-3-oxopiperazine-1-carboxylatewas hydrolyzed via Procedure M to give4-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)benzoic acid. 200mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to4-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)benzoic acid viaProcedure G. The crude product was extracted twice with saturatedbicarbonate in Ethyl Acetate, dried over Magnesium Sulfate, filtered andconcentrated to give crude tert-butyl4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)-3-oxopiperazine-1-carboxylate.4N HCl was subsequently added to crude tert-butyl4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)-3-oxopiperazine-1-carboxylateand concentrated to give the HC salt ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide.The reaction was purified by reverse phase HPLC to give pureN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide.MS (Q1) 421.3 (M)⁺.

Example 171N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-2-oxopiperazin-1-yl)methyl)benzamide

To 200 mg of the HCl salt ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamidewas added 55 mg of Paraformaldehyde and 185 mg of SodiumTriacetoxyborohydride in 1 mL of 2% AcOH in DMF. After completion, thereaction is extracted once with bicarbonate and brine in Ethyl Acetate,dried over Magnesium Sulfate, concentrated and purified by reverse phaseHPLC to give pureN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-2-oxopiperazin-1-yl)methyl)benzamide.MS (Q1) 435.3 (M)⁺.

Example 1722-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)benzamide

100 mg of the crude HCl salt of4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamidewas reacted with 72 mg of1-(4,5-dihydro-1H-imidazol-2-yl)-3,5-dimethyl-1H-pyrazole and 100 μL ofDIPEA in 500 μL of DMF in the microwave at 150° C. for 5 minutes. Thecrude product was concentrated to dryness and purified by reverse phaseHPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)benzamide.MS (Q1) 440 (M)⁺.

Example 173N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)benzamide

100 mg of the crude HCl salt of4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reactedwith 80 mg of 1-(4,5-dihydro-1H-imidazol-2-yl)-3,5-dimethyl-1H-pyrazoleand 110 μL of DIPEA in 1 mL of DMF in the microwave at 150° C. for 5minutes. The crude product was concentrated to dryness and purified byreverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)benzamide.MS (Q1) 406 (M)⁺.

Example 174N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((pyridin-2-ylsulfonyl)methyl)benzamide

500 mg of methyl 4-(bromomethyl)benzoate was reacted withpyridine-2-thiol via Procedure Q. 260 mg of methyl4-((pyridin-2-ylthio)methyl)benzoate was reacted via Procedure R to givemethyl 4-((pyridin-2-ylsulfonyl)methyl)benzoate. 275 mg of methyl4-((pyridin-2-ylsulfonyl)methyl)benzoate was hydrolyzed via Procedure Mto give 4-((pyridin-2-ylsulfonyl)methyl)benzoic acid. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-((pyridin-2-ylsulfonyl)methyl)benzoic acid via Procedure G. The crudeproduct was purified by reverse phase HPLC to yield pureN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((pyridin-2-ylsulfonyl)methyl)benzamide.MS (Q1) 464.1 (M)⁺.

Example 175N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methylmethylsulfonamido)benzamide

500 mg of methyl 4-(methylamino)benzoate was cooled to 0° C. in DCM with270 μL of Pyridine before 260 μL Methanesulfonyl Chloride was addeddropwise. Reaction was allowed to warm to room temperature and stirovernight. Solvent was concentrated and the crude material was dissolvedin Ethyl Acetate and extracted with 0.1N NaOH solution twice. Crudematerial was dried over Magnesium Sulfate, filtered and concentrated togive methyl 4-(N-methylmethylsulfonamido)benzoate. 698 mg of methyl4-(N-methylmethylsulfonamido)benzoate was hydrolyzed via Procedure M togive 4-(N-methylmethylsulfonamido)benzoic acid. 100 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(N-methylmethylsulfonamido)benzoic acid via Procedure G. The crudeproduct was purified by reverse phase HPLC to yield pureN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methylmethylsulfonamido)benzamide.MS (Q1) 416.3 (M)⁺.

Example 1762-bromo-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide

1.2 g of 2-bromo-4-methylbenzoic acid was brominated via Procedure N.100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 160 mg of2-bromo-4-(bromomethyl)benzoic acid via Procedure E. 213 mg of2-bromo-4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide wasreacted via Procedure O to give2-bromo-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamidewhich was purified by reverse phase HPLC to afford pure2-bromo-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide.MS (Q1) 481.2 (M)⁺.

Example 1774-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

500 mg of methyl 4-(bromomethyl)benzoate was reacted with4H-1,2,4-triazole-3-thiol via Procedure Q. 542 mg of methyl4-((4H-1,2,4-triazol-3-ylthio)methyl)benzoate was subsequently reactedvia Procedure R to give an approximate 1:9 mixture of methyl4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoate and methyl4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoate. The mixture of 467 mgwas hydrolyzed via Procedure M to give4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid. 107 mg of themixture of 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid was coupled to 75mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture wasseparated on reverse phase HPLC to give4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 438.1 (M)⁺.

Example 1784-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-benzamide

107 mg of a mixture of 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoicacid and 4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid wascoupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G.The mixture was separated on reverse phase HPLC to give4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 454.3 (M)⁺.

Example 179N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)-methyl)benzamide

500 mg of methyl 4-(bromomethyl)benzoate was reacted with4-methyl-4H-1,2,4-triazole-3-thiol via Procedure Q. 804 mg of methyl4-((4-methyl-4H-1,2,4-triazol-3-ylthio)methyl)benzoate was subsequentlyreacted via Procedure R to give an approximate 1:9 mixture of methyl4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoate and methyl4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoate. The mixtureof 740 mg was hydrolyzed via Procedure M to give4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid. 114 mgof the mixture of4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid wascoupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G.The mixture was separated on reverse phase HPLC to giveN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzamide.MS (Q1) 452.3 (M)⁺.

Example 180N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)-methyl)benzamide

114 mg of the mixture of4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid wascoupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G.The mixture was separated on reverse phase HPLC to giveN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzamide.MS (Q1) 468.1 (M)⁺.

Example 181N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(methylsulfonylmethyl)benzamide

300 mg of methyl 3-(bromomethyl)benzoate was reacted via Procedure O togive methyl 3-(methylsulfonylmethyl)benzoate. 230 mg of methyl3-(methylsulfonylmethyl)benzoate was reacted via Procedure M to give3-(methylsulfonylmethyl)benzoic acid.

75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to3-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude productwas purified by reverse phase HPLC to yield pureN-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(methylsulfonylmethyl)benzamide.MS (Q1) 401 (M)⁺.

Example 182N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methoxy-4-(methylsulfonylmethyl)benzamide

900 mg of 2-methoxy-4-methylbenzoic acid was brominated via Procedure Nto afford 4-(bromomethyl)-2-methoxybenzoic acid. 100 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to 132 mg of4-(bromomethyl)-2-methoxybenzoic acid via Procedure E. 211 mg of4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methoxybenzamidewas reacted via Procedure O and purified by reverse phase HPLC to yieldpureN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methoxy-4-(methylsulfonylmethyl)benzamide.MS (Q1) 431 (M)⁺.

Example 183N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1-(methylsulfonyl)ethyl)benzamide

75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 93 mg of4-(1-bromoethyl)benzoic acid via Procedure E. 153 mg of4-(1-bromoethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide wasreacted via Procedure O and purified by reverse phase HPLC to give pureN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1-(methylsulfonyl)ethyl)benzamide.MS (Q1) 415.3 (M)⁺.

Example 184 ethyl4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl(methyl)phosphinate

90 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamidewas reacted with 45 μL of diethyl methylphosphonite in the microwave at120° C. for 5 minutes. The reaction was evaporated to dryness andpurified by reverse phase HPLC to give pure ethyl4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl(methyl)phosphinate.MS (Q1) 429 (M)⁺.

Example 185N-(4-chloro-3-(5-(hydroxymethyl)pyridin-2-yl)phenyl)-4-(methylsulfonyl-methyl)benzamide

75 mL of (5-methylpyridin-2-yl)zinc(II) bromide was reacted with 4 g of1-chloro-2-iodo-4-nitrobenzene via Procedure B. To 935 mg of2-(2-chloro-5-nitrophenyl)-5-methylpyridine in 5 mL of Sulfuric Acid wasslowly added 2.25 g of Chromium (III) Oxide and the reaction was stirredfor several hours at room temperature until complete. Icewater was addedto dilute the reaction and the aqueous layer was extracted 3 times withEthyl Acetate. The organic layers were combined, dried over MagnesiumSulfate, filtered and concentrated to give6-(2-chloro-5-nitrophenyl)nicotinic acid. 704 mg of6-(2-chloro-5-nitrophenyl)nicotinic acid was esterified with 3.1 mL of4N HCl in Dioxane in 20 mL of MeOH. The reaction was concentrated andsubjected to basic workup, dried over Magnesium Sulfate, filtered andconcentrated to give methyl 6-(2-chloro-5-nitrophenyl)nicotinate. 681 mgof methyl 6-(2-chloro-5-nitrophenyl)nicotinate was treated with 2.1 g ofTin (II) Chloride and 1 mL of HCl in 25 mL of EtOH. Upon completion,EtOH was concentrated and the reaction was extracted with Ethyl Acetateand water with TEA to decrease emulsions. The organic layer was driedover Magnesium Sulfate, filtered and concentrated to give crude methyl6-(5-amino-2-chlorophenyl)nicotinate. 296 mg of methyl6-(5-amino-2-chlorophenyl)nicotinate was coupled to 266 mg of4-(methylsulfonylmethyl)benzoic acid via Procedure G. To 518 mg ofmethyl6-(2-chloro-5-(4-(methylsulfonylmethyl)benzamido)phenyl)nicotinate at 0°C. in 20 mL of EtOH was slowly added 640 mg of Sodium Borohydride. Thereaction was subsequently refluxed for 1 hour until complete, quenchedwith water and extracted with Ethyl Acetate. The organic layer was driedover Magnesium Sulfate, filtered, concentrated and purified by reversephase HPLC to give pureN-(4-chloro-3-(5-(hydroxymethyl)pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide.MS (Q1) 431.1 (M)⁺.

Example 1866-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)nicotinate

200 mg of methyl 6-(5-amino-2-chlorophenyl)nicotinate was treated with255 μL of 2-methyl-6-(trifluoromethyl)nicotinoyl chloride via ProcedureD and purified by reverse phase HPLC to give pure6-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)nicotinate.MS (Q1) 450 (M)⁺.

Example 187N-(4-chloro-3-(5-(hydroxymethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide

To 110 mg of methyl6-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)nicotinateat 0° C. in 5 mL of EtOH was slowly added 148 mg of Sodium Borohydride.The reaction was subsequently refluxed for 1 hour until complete,quenched with water and extracted with Ethyl Acetate. The organic layerwas dried over Magnesium Sulfate, filtered, concentrated and purified byreverse phase HPLC to give pureN-(4-chloro-3-(5-(hydroxymethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide.MS (Q1) 422.1 (M)⁺.

Example 188N-(4-chloro-3-(5-(methylcarbamoyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide

120 mg of6-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)nicotinatewas hydrolyzed via Procedure M. 112 mg of6-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)nicotinicacid was coupled to Methylamine Hydrochloride via Procedure G andpurified by reverse phase HPLC to give pureN-(4-chloro-3-(5-(methylcarbamoyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide.MS (Q1) 449 (M)⁺.

Example 1892-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,2,2-trifluoroethylamino)methyl)benzamide

To 24.9 g of 2-chloro-4-(methoxycarbonyl)benzoic acid and 2 mL ofSulfuric Acid in 350 mL of DCM was added isobutylene gas at −78° C.until the solvent was saturated and capped off securely. Let go severaldays at room temperature and re-cool to −78° C. before removing cap.Concentrate solvent, extract with Ethyl Acetate and bicarbonate, drywith Magnesium Sulfate, filter and concentrate to give 31.4 g of1-tert-butyl 4-methyl 2-chloroterephthalate. 3.35 g of 1-tert-butyl4-methyl 2-chloroterephthalate was hydrolyzed via Procedure M. 2.5 g of4-(tert-butoxycarbonyl)-3-chlorobenzoic acid was cooled to 0° C. in 25mL of THF before a solution of 19.5 mL of 1M BH₃-THF complex in THF wasadded dropwise. The ice bath was subsequently removed and the reactionwas stirred at room temperature until reaction stalled out at ˜50%complete by TLC. The reaction is re-cooled to 0° C. and another 19.5 mLof BH₃-THF is added dropwise before the ice bath is removed. Uponcompletion, the reaction is re-cooled to 0° C. and quenched with 3N HCldropwise. The aqueous layer was extracted two times with Ethyl Acetateand the organic layer was then extracted once with bicarbonate solutionand brine, dried over Magnesium Sulfate, filtered and concentrated togive tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 564 mg of tert-butyl2-chloro-4-(hydroxymethyl)benzoate was cooled to 0° C. in 5 mL of DCMbefore adding 665 mg of Triphenylphosphine and 417 mg of NBS. Reactionwas concentrated and directly purified via ISCO Combi-Flash to give puretert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 147 mg of tert-butyl4-(bromomethyl)-2-chlorobenzoate was reacted with2,2,2-trifluoroethanamine in DMSO via Procedure P. 141 mg of tert-butyl2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoate was treated with4N HCl in Dioxane at 45° C. and concentrated to give2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid. 50 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to 75 mg of2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid via ProcedureG. The crude product was purified by reverse phase HPLC to give pure2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,2,2-trifluoroethylamino)methyl)benzamide.MS (Q1) 454.6 (M)⁺.

Example 1902-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide

3.01 g of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted viaProcedure O to give tert-butyl2-chloro-4-(methylsulfonylmethyl)benzoate. 1.2 g of tert-butyl2-chloro-4-(methylsulfonylmethyl)benzoate was treated with 10 mL of 4NHCl in Dioxane at 45° C. and concentrated upon completion to give crude2-chloro-4-(methylsulfonylmethyl)benzoic acid. 775 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to 1 g of2-chloro-4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crudeproduct was purified by reverse phase HPLC to give pure2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide.MS (Q1) 435 (M)⁺.

Example 191N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(methylsulfonamido)nicotinamide

100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide wasreacted with methanesulfonamide and 108 μL of2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorinevia Procedure F. The crude reaction was concentrated to dryness andpurified by reverse phase HPLC to give pureN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(methylsulfonamido)nicotinamide.MS (Q1) 403 (M)⁺.

Example 1924-((1H-1,2,4-triazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

88 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamidewas coupled to 45 mg of 1H-1,2,4-triazole via Procedure P. The reactionwas evaporated to dryness and purified by reverse phase HPLC to yield4-((1H-1,2,4-triazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 390 (M)⁺.

Example 1934-((1H-1,2,3-triazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

88 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamidewas coupled to 40 μL of 1H-1,2,3-triazole via Procedure P. The reactionwas evaporated to dryness and purified by reverse phase HPLC to yield4-((1H-1,2,3-triazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 390.1 (M)⁺.

Example 194N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide

70 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamidewas coupled to 50 mg of 3,5-dimethyl-1H-pyrazole via Procedure P. Thereaction was evaporated to dryness and purified by reverse phase HPLC toyieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide.MS (Q1) 417.3 (M)⁺.

Example 1954-((1H-pyrazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

70 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamidewas coupled to 36 mg of 1H-pyrazole via Procedure P. The reaction wasevaporated to dryness and purified by reverse phase HPLC to yield4-((1H-pyrazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 389.3 (M)⁺.

Example 196N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(methylsulfonylmethyl)nicotinamide

1.2 g of 6-methylnicotinic acid was brominated via Procedure N to give6-(bromomethyl)nicotinic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)anilinewas coupled to 87 mg of 6-(bromomethyl)nicotinic acid via Procedure E.145 mg of6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide wasreacted via Procedure O and purified by reverse phase HPLC to yield pureN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(methylsulfonylmethyl)nicotinamide.MS (Q1) 402 (M)⁺.

Example 197N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-hydroxycarbamimidoyl)benzamide

240 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 207 mg of4-cyanobenzoic acid via Procedure G. To 445 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide and 2.5 mL of DIPEAin 10 mL of EtOH was added 793 mg Hydroxylamine Hydrochloride and heatedto 60° C. until reaction was complete. The solvent was subsequentlyevaporated, extracted twice with water in Ethyl Acetate, dried withMagnesium Sulfate, filtered and concentrated. The crude product waspurified by reverse phase HPLC to give pureN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-hydroxycarbamimidoyl)benzamide.MS (Q1) 367.4 (M)⁺.

Example 198N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methoxycarbamimidoyl)benzamide

100 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-hydroxycarbamimidoyl)benzamidewas cooled to 0° C. in 1.5 mL of Dioxane. 5 mL of 2N NaOH was slowlyadded followed by dropwise addition of 33 μL of dimethylsulfate. The icebath was removed and reaction was stirred at room temperature for 1hour. The reaction was subsequently evaporated and extracted with watertwice in Ethyl Acetate, dried with Magnesium Sulfate, filtered andconcentrated to yield pureN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methoxycarbamimidoyl)benzamide.MS (Q1) 381 (M)⁺.

Example 199N-(4-chloro-3-(4-(hydroxymethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide

75 mL of (4-methylpyridin-2-yl)zinc(II) bromide was reacted with 4 g of1-chloro-2-iodo-4-nitrobenzene via Procedure B. To 300 mg of2-(2-chloro-5-nitrophenyl)-4-methylpyridine in 1.5 mL of Sulfuric Acidwas slowly added 362 mg of Chromium (III) Oxide and the reaction wasstirred for several hours at room temperature until complete. Icewaterwas added to dilute the reaction and the aqueous layer was extracted 3times with Ethyl Acetate. The organic layers were combined, dried overMagnesium Sulfate, filtered and concentrated to give2-(2-chloro-5-nitrophenyl)isonicotinic acid. 300 mg of2-(2-chloro-5-nitrophenyl)isonicotinic acid was esterified with 750 μLof 4N HCl in Dioxane in 10 mL of MeOH at 55° C. for 16 hours. Thereaction was concentrated and subjected to basic workup, dried overMagnesium Sulfate, filtered and concentrated to give methyl2-(2-chloro-5-nitrophenyl)isonicotinate. 259 mg of methyl2-(2-chloro-5-nitrophenyl)isonicotinate was treated with 200 mg of Tin(II) Chloride and 500 μL of HCl in 10 mL of EtOH. Upon completion, EtOHwas concentrated and the reaction was extracted with Ethyl Acetate andwater with TEA to decrease emulsions. The organic layer was dried overMagnesium Sulfate, filtered and concentrated to give crude methyl2-(5-amino-2-chlorophenyl)isonicotinate. 240 mg of methyl methyl2-(5-amino-2-chlorophenyl)isonicotinate was treated with 204 μL of2-methyl-6-(trifluoromethyl)nicotinoyl chloride via Procedure D. To 100mg of methyl2-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)isonicotinateat 0° C. in 5 mL of EtOH was slowly added 135 mg of Sodium Borohydride.The reaction was subsequently refluxed for 1 hour until complete,quenched with water and extracted with Ethyl Acetate. The organic layerwas dried over Magnesium Sulfate, filtered, concentrated and purified byreverse phase HPLC to give pureN-(4-chloro-3-(4-(hydroxymethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide.MS (Q1) 422.1 (M)⁺.

Example 200N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylamide)benzamide

300 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 270 mg of4-nitrobenzoic acid via Procedure G. To 520 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-nitrobenzamide in 2.5 mL of HCl in10 mL of EtOH was added 1.3 g of Tin (II) Chloride and stirred at 55° C.Upon completion, the reaction was concentrated and extracted with EthylAcetate in water with TEA to reduce emulsions. The organic layer wasdried over Magnesium Sulfate, filtered and concentrated to give4-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 100 mg of4-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 30μL of Methanesulfonyl Chloride and 90 μL DIPEA in 500 μL DCM. Thereaction mixture was evaporated, subjected to basic workup conditionsand purified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylamide)benzamide. MS(Q1) 402 (M)⁺.

Example 201N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1-methylethylsulfonamido)benzamide

151 mg of 4-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide wasreacted with 105 μL of propane-2-sulfonyl chloride and 205 μL DIPEA in500 μL DCM. The reaction mixture was evaporated, subjected to basicworkup conditions and purified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1-methylethylsulfonamido)benzamide.MS (Q1) 430 (M)⁺.

Example 202N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide

1 g of methyl 4-(bromomethyl)benzoate was reacted via Procedure O. 2.77g of methyl 4-(methylsulfonylmethyl)benzoate was hydrolyzed viaProcedure M. 1 g of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 1.15g of 4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crudeproduct was subjected to basic workup and recrystallized with 1:1 Ratioof Isopropylacetate and Ether to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide.MS (Q1) 401 (M)⁺.

Example 2034-(4-acetylpiperazin-1-ylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 646 μL of1-(piperazin-1-yl)ethanone via Procedure H. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to 125 mg of4-(4-acetylpiperazin-1-ylsulfonyl)benzoic acid via Procedure G andpurified by reverse phase HPLC to yield4-(4-acetylpiperazin-1-ylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 499.4 (M)⁺.

Example 204N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)benzamide

1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 615 μL of2-(piperazin-1-yl)ethanol via Procedure H. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to 125 mg of4-(4-(3-hydroxypropyl)piperazin-1-ylsulfonyl)benzoic acid by Procedure Gand purified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)benzamide.MS (Q1) 501.3 (M)⁺.

Example 205N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-hydroxypiperidin-1-ylsulfonyl)benzamide

1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 506 μL ofpiperidin-4-ol via Procedure H. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to 114 mg of4-(4-hydroxypiperidin-1-ylsulfonyl)benzoic acid via Procedure G andpurified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-hydroxypiperidin-1-ylsulfonyl)benzamide.MS (Q1) 472.3 (M)⁺.

Example 206N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2,6-dimethylmorpholinosulfonyl)benzamide

1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 616 μL of2,6-dimethylmorpholine via Procedure H. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to 120 mg of4-(2,6-dimethylmorpholinosulfonyl)benzoic acid via Procedure G andpurified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2,6-dimethylmorpholinosulfonyl)benzamide.MS (Q1) 486.3 (M)⁺.

Example 207N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3,5-dimethylpiperazin-1-ylsulfonyl)benzamide

1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 570 mg of2,6-dimethylpiperazine via Procedure H. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to 119 mg of4-(3,5-dimethylpiperazin-1-ylsulfonyl)benzoic acid via Procedure G andpurified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3,5-dimethylpiperazin-1-ylsulfonyl)benzamide.MS (Q1) 485.4 (M)⁺.

Example 208N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-ethylpiperazin-1-ylsulfonyl)benzamide

1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 570 mg of1-ethylpiperazine via Procedure H. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(4-ethylpiperazin-1-ylsulfonyl)benzoic acid via Procedure G andpurified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-ethylpiperazin-1-ylsulfonyl).MS (Q1) 485 (M)⁺.

Example 209N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(piperazin-1-ylsulfonyl)benzamide

1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 931 mg oftert-butyl piperazine-1-carboxylate via Procedure H. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to 150 mg of4-(4-(tert-butoxycarbonyl)piperazin-1-ylsulfonyl)benzoic acid viaProcedure G. The crude product was subjected to basic workup conditions,treated with TFA to remove the Boc group and purified by reverse phaseHPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(piperazin-1-ylsulfonyl)benzamide.MS (Q1) 457.1 (M)⁺.

Example 210N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2,2,2-trifluoroethyl)sulfamoyl)benzamide

1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 500 μL of2,2,2-trifluoroethanamine via Procedure H. 60 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to 92 mg of4-(N-(2,2,2-trifluoroethyl)sulfamoyl)benzoic acid by Procedure G andpurified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2,2,2-trifluoroethyl)sulfamoyl)benzamide.MS (Q1) 470 (M)⁺.

Example 2112-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-sulfamoylbenzamide

A solution of 818 mg of Sodium Nitrite in 13 mL of water was addeddropwise to a solution of 2 g of methyl 4-amino-2-chlorobenzoate in 5 mLof HCl and 15 mL of AcOH at 0° C. The reaction was removed from the icebath and stirred at room temperature for 15 minutes. Simultaneously asolution of 460 mg of Copper II Chloride Dihydrate in 1 mL of water wasadded to a saturated solution of sulfur dioxide gas in 10 mL of AcOH at0° C. The cooled solution containing Copper II Chloride and sulfurdioxide gas was slowly added to the re-cooled initial solutioncontaining Sodium Nitrite. The reaction was warmed to room temperatureand stirred until gas no longer evolved. The reaction was filteredthrough celite and poured into a beaker of stirred icewater until ayellow-orange solid crashed out. The icewater solution was filtered thrua Buchner funnel to collect the methyl2-chloro-4-(chlorosulfonyl)benzoate precipitate and was dried for 24hours under vacuum. 1 g of methyl 2-chloro-4-(chlorosulfonyl)benzoatewas added to a solution of 2 mL of 2M solution of Ammonia in MeOH and970 μL DIPEA in 5 mL MeOH. Upon completion the reaction wasconcentrated, extracted twice with saturated bicarbonate, dried withMagnesium Sulfate, filtered and concentrated to give methyl2-chloro-4-sulfamoylbenzoate. 777 mg of methyl2-chloro-4-sulfamoylbenzoate was hydrolyzed via Procedure M to yieldcrude 2-chloro-4-sulfamoylbenzoic acid. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to 91 mg of crude2-chloro-4-sulfamoylbenzoic acid via Procedure G. The crude product waspurified by reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-sulfamoylbenzamide. MS(Q1) 422 (M)⁺.

Example 212N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(piperidin-4-ylmethyl)benzamide

75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 125 mg of4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)benzoic acid viaProcedure G. The crude product was treated with 4N HCl in Dioxane,evaporated and purified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(piperidin-4-ylmethyl)benzamide.MS (Q1) 406.1 (M)⁺.

Example 2132-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonamido)benzamide

4.2 g of methyl 2-chloro-4-(methylsulfonamido)benzoate was hydrolyzedvia Procedure M. 1 g of 4-chloro-3-(pyridin-2-yl)aniline was coupled to1.35 g of 2-chloro-4-(methylsulfonamido)benzoic acid via Procedure G.The crude product was purified by reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonamido)benzamide.MS (Q1) 436.1 (M)⁺.

Example 214N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1H-imidazol-1-yl)benzamide

75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 78 mg of4-(1H-imidazol-1-yl)benzoic acid via Procedure G. The crude product waspurified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1H-imidazol-1-yl)benzamide. MS(Q1) 375.3 (M)⁺.

Example 2152-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-methylpropylsulfonyl)-benzamide

8 g of methyl 4-amino-2-chlorobenzoate was dissolved in 16 mL of MeOH, 8mL of H₂O and 8 mL of concentrated hydrochloric acid and was then cooledto 0 ^(□)C. A solution of 3.9 g of sodium nitrite in 15 mL of H₂O wasadded dropwise over 30 min. The reaction was stirred at 0° C. for anadditional 1 h. The cold diazonating mixture was added to a solution of13.8 g of potassium ethyl xanthate in 10 mL of H₂O at 50-60° C. Thereaction was heated to 65° C. for 2 h and monitored by TLC untilcomplete. The mixture was cooled to 25° C. and extracted with ethylacetate. The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated. Purified by silica gel chromatography (0-10%ethyl acetate/hexane) to afford methyl2-chloro-4-(ethoxycarbonothioylthio)benzoate. A solution of 2.6 g ofsodium hydroxide in 20 mL of H₂O was added to 5.9 g of methyl2-chloro-4-(ethoxycarbonothioylthio)benzoate in 40 mL of EtOH Thereaction mixture was heated to 70° C. for 1 h. Upon completion, themixture was cooled to 25° C., and then acidified to pH 3 by the additionof 10 N HCl. The solid was filtered and washed with H₂O to give2-chloro-4-mercaptobenzonic acid. 3.8 g of 2-chloro-4-mercaptobenzonicacid in 40 mL of 5% sulfuric acid-methanol was refluxed under nitrogenatmosphere for 3 h. After concentration of the reaction mixture, 10 mLof H₂O was added and the resulting mixture was made alkaline with sodiumhydrogen carbonate, and extracted with ethyl acetate. The organic layerwas washed with brine, dried (MgSO₄), and evaporated to yield methyl2-chloro-4-mercaptobenzoate. 80 mg of isobutylene oxide was reacted withmethyl 2-chloro-4-mercaptobenzoate via Procedure S to afford methyl2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate. 190 mg of methyl2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate was hydrolyzed viaProcedure M to give 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoicacid. 160 mg of 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acidwas reacted via procedure R to give2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid. 60 mg of4-chloro-3-(pyridine-2-yl)aniline was coupled to2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid via ProcedureG. The product was purified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-methylpropylsulfonyl)benzamide.MS (Q1) 479.1 (M)⁺.

Example 216(R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-phenylethylsulfonyl)benzamide

150 mg of (R)-styrene oxide was reacted with methyl2-chloro-4-mercaptobenzoate via Procedure S to afford (R)-methyl2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate. 190 mg of(R)-methyl-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate washydrolyzed via Procedure M to give(R)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid. 170 mg of(R)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid was reacted viaProcedure R to give(R)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid. 60 mg of4-chloro-3-(pyridine-2-yl)aniline was coupled to(R)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid viaProcedure G. The product was purified on reverse phase HPLC to yield(R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-phenylethylsulfonyl)benzamide.MS (Q1) 527.2 (M)⁺.

Example 217(S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-phenylethyl-sulfonyl)benzamide

119 mg of (S)-styrene oxide was reacted with methyl2-chloro-4-mercaptobenzoate via Procedure S to afford (S)-methyl2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate. 230 mg of(S)-methyl-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate washydrolyzed via Procedure M to give(S)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid. 180 mg of(S)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid was reacted viaProcedure R to give(S)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid. 60 mg of4-chloro-3-(pyridine-2-yl)aniline was coupled to(S)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid viaProcedure G. The product was purified on reverse phase HPLC to yield(S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-phenylethylsulfonyl)benzamide.MS (Q1) 527.0 (M)⁺.

Example 218(R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)-benzamide

140 mg of (R)-propylene oxide was reacted with methyl2-chloro-4-mercaptobenzoate via Procedure S to afford (R)-methyl2-chloro-4-(2-hydroxypropylthio)benzoate. 435 mg of(R)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed viaProcedure M to give (R)-2-chloro-4-(2-hydroxypropylthio)benzoic acid.403 mg of (R)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reactedvia Procedure R to give (R)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoicacid. 298 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to(R)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G.The product was purified on reverse phase HPLC to yield(R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide.MS (Q1) 465.1 (M)⁺.

Example 219(S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)-benzamide

86 mg of (S)-propylene oxide was reacted with methyl2-chloro-4-mercaptobenzoate via Procedure S to afford (S)-methyl2-chloro-4-(2-hydroxypropylthio)benzoate. 275 mg of(S)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed viaProcedure M to give (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid.220 mg of (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reactedvia Procedure R to give (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoicacid. 70 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to(S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G.The product was purified on reverse phase HPLC to yield(S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide.MS (Q1) 465.0 (M)⁺.

Example 220(R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide

100 mg of (R)-propylene oxide was reacted with methyl 4-mercaptobenzoatevia Procedure S to afford (R)-methyl 4-(2-hydroxypropylthio)benzoate.169 mg of (R)-methyl 4-(2-hydroxypropylthio)benzoate was reacted viaProcedure R to give (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 179mg of (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed viaProcedure M to give (R)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mgof 4-chloro-3-(pyridine-2-yl)aniline was coupled to(R)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The productwas purified on reverse phase HPLC to yield(R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide.MS (Q1) 431.2 (M)⁺.

Example 221(S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide

150 mg of (S)-propylene oxide was reacted with methyl 4-mercaptobenzoatevia Procedure S to afford (S)-methyl 4-(2-hydroxypropylthio)benzoate.650 mg of (S)-methyl 4-(2-hydroxypropylthio)benzoate was reacted viaProcedure R to give (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 350mg of (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed viaProcedure M to give (S)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mgof 4-chloro-3-(pyridine-2-yl)aniline was coupled to(S)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The productwas purified on reverse phase HPLC to yield(S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide.MS (Q1) 431.3 (M)⁺.

Example 222N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyridin-3-ylmethylsulfonyl)benzamide

1 g of 3-(bromomethyl)pyridine hydrobromide was reacted with methyl4-mercaptobenzoate via Procedure Q to afford methyl4-(pyridin-3-ylmethylthio)benzoate. 980 mg of methyl4-(pyridin-3-ylmethylthio)benzoate was reacted via Procedure R to givemethyl 4-(pyridin-3-ylmethylsulfonyl)benzoate. 760 mg of methyl4-(pyridin-3-ylmethylsulfonyl)benzoate was hydrolyzed via Procedure M togive 4-(pyridin-3-ylmethylsulfonyl)benzoic acid. 60 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(pyridin-3-ylmethylsulfonyl)benzoic acid via Procedure G. The productwas purified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyridin-3-ylmethylsulfonyl)benzamide.MS (Q1) 464.1 (M)⁺.

Example 223N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyridin-2-ylmethylsulfonyl)benzamide

1 g of 2-(bromomethyl)pyridine hydrobromide was reacted with methyl4-mercaptobenzoate via Procedure Q to afford methyl4-(pyridin-2-ylmethylthio)benzoate. 500 mg of methyl4-(pyridin-2-ylmethylthio)benzoate was reacted via Procedure R to givemethyl 4-(pyridin-2-ylmethylsulfonyl)benzoate. 470 mg of methyl4-(pyridin-2-ylmethylsulfonyl)benzoate was hydrolyzed via Procedure M togive 4-(pyridin-2-ylmethylsulfonyl)benzoic acid. 70 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(pyridin-2-ylmethylsulfonyl)benzoic acid via Procedure G. The productwas purified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyridin-2-ylmethylsulfonyl)benzamide.MS (Q1) 464.1 (M)⁺.

Example 2244-(2-amino-2-oxoethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

2.5 g of 2-bromoacetamide was reacted with methyl 4-mercaptobenzoate viaProcedure Q to afford methyl 4-(2-amino-2-oxoethylthio)benzoate. 2.6 gof methyl 4-(2-amino-2-oxoethylthio)benzoate was reacted via Procedure Rto give methyl 4-(2-amino-2-oxoethylsulfonyl)benzoate. 1 g of methyl4-(2-amino-2-oxoethylsulfonyl)benzoate was hydrolyzed via Procedure M togive 4-(2-amino-2-oxoethylsulfonyl)benzoic acid. 150 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(2-amino-2-oxoethylsulfonyl)benzoic acid via Procedure G. The productwas purified on reverse phase HPLC to yield4-(2-amino-2-oxoethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 430.2 (M)⁺.

Example 2252-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide

2 g of 2-chloro-4-fluorobenzonitrile was reacted with1-mercapto-2-propanol via Procedure Q to afford2-chloro-4-(2-hydroxypropylthio)benzonitrile. 2.5 g of2-chloro-4-(2-hydroxypropylthio)benzonitrile was reacted via Procedure Tto give 2-chloro-4-(2-hydroxypropylthio)benzoic acid. 2.1 g of2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure Rto give 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 70 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide.MS (Q1) 465.2 (M)⁺.

Example 226N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)-2-methylbenzamide

2 g of 4-bromo-2-methylbenzonitrile was reacted with1-mercapto-2-propanol via Procedure Q to afford4-(2-hydroxypropylthio)-2-methylbenzonitrile. 950 mg of4-(2-hydroxypropylthio)-2-methylbenzonitrile was reacted via Procedure Tto give 4-(2-hydroxypropylthio)-2-methylbenzoic acid. 1.0 g of4-(2-hydroxypropylthio)-2-methylbenzoic acid was reacted via Procedure Rto give 4-(2-hydroxypropylsulfonyl)-2-methylbenzoic acid. 100 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(2-hydroxypropylsulfonyl)-2-methylbenzoic acid via Procedure G. Theproduct was purified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)-2-methylbenzamide.MS (Q1) 445.3 (M)⁺.

Example 227N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide

5 g of 4-fluorobenzonitrile was used in Procedure Q with2-mercaptoethanol to afford 4-(2-hydroxyethylthio)benzonitrile. 900 mgof 4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure T togive 4-(2-hydroxyethylthio)benzoic acid. 1.0 g of4-(2-hydroxyethylthio)benzoic acid was reacted via Procedure R to give4-(2-hydroxyethylsulfonyl)benzoic acid. 80 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(2-hydroxyethylsulfonyl)benzoic acid via Procedure G. The product waspurified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide.MS (Q1) 417.0 (M)⁺.

Example 2284-(2-(1H-imidazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

4 g of 4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure R toyield 4-(2-hydroxyethylsulfonyl)benzonitrile. 3.0 g oftriphenylphosphine was added to a solution of 2 g of4-(2-hydroxyethylsulfonyl)benzonitrile and 4.7 g of carbon tetrabromidein dichloromethane at 0° C. The reaction mixture was allowed to warm toroom temperature and stirred for 1 h. The mixture was diluted withdichloromethane, washed with H₂O, dried (MgSO₄) and evaporated. Purifiedby silica gel chromatography (0-70% ethyl acetate/hexane) to afford4-(2-bromoethylsulfonyl)benzonitrile. 250 mg of4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P withimidazole to give 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzonitrile. 300mg of 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzonitrile was reacted viaProcedure T to give 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzoic acid.60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzoic acid via Procedure G. Theproduct was purified on reverse phase HPLC to yield4-(2-(1H-imidazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 467.1 (M)⁺.

Example 2294-(2-(1H-pyrazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

250 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure Pwith pyrazole to yield4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile. 300 mg of4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile was reacted viaProcedure T to give 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid.75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid via Procedure G. Theproduct was purified on reverse phase HPLC to yield4-(2-(1H-pyrazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 467.0 (M)⁺.

Example 230N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-(4-methyl-1H-imidazol-1-yl)ethylsulfonyl)benzamide

270 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure Pwith 4-methylimidazole to yield4-(2-(4-methyl-1H-imidazole-1-yl)ethylsulfonyl)benzonitrile. 320 mg of4-(2-(4-methyl-1H-imidazole-1-yl)ethylsulfonyl)benzonitrile was reactedvia Procedure T to give4-(2-(4-methyl-1H-imidazole-1-yl)ethylsulfonyl)benzoic acid.

70 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(2-(4-methyl-1H-imidazole-1-yl)ethylsulfonyl)benzoic acid viaProcedure G. The product was purified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-(4-methyl-1H-imidazol-1-yl)ethylsulfonyl)benzamide.MS (Q1) 481.0 (M)⁺.

Example 231N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)ethylsulfonyl)benzamide

To a stirred suspension of 10 g of thiosemicarbazide in 100 mL ofpyridine was slowly added 7.8 ml of acetyl chloride at 0° C. Thetemperature was maintained throughout the addition (0° C.-4° C.). Thereaction mixture was allowed to warm to room temperature and stirred for16 h. Evaporation gave 1-acetyl thiosemicarbazide. The crude 1-acetylthiosemicarbazide was dissolved in 70 mL of MeOH and 12 g of sodiummethoxide, and was refluxed for 10 h. The solvent was removed and theresidue was dissolved in H₂O, then acidified to pH 2 by the addition of1N HCl. The resulting solid was filtered and washed with H₂O to give3-methyl-1,2,4-triazole-5-thiol. 1 g of 3-methyl-1,2,4-triazole-5-thiolwas added to a solution of 61 mg of sodium nitrite in 3 ml of nitricacid and 6 mL of H₂O at 0° C. The reaction-mixture was stirred for 1 hat 0° C., and basified with saturated sodium carbonate and concentrated.The residue was dissolved with MeOH and filtered. The filtrate wasevaporated to give 3-methyl-1,2,4-triazole. 230 mg of4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with3-methyl-1,2,4-triazole to yield4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzonitrile. 310 mgof 4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzonitrile wasreacted via Procedure T to give4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzoic acid.

60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)ethylsulfonyl)benzoic acid viaProcedure G. The product was purified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)ethylsulfonyl)benzamide.MS (Q1) 482.1 (M)⁺.

Example 232N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide

5 g of 4-fluorobenzonitrile was used in Procedure Q with3-mercapto-1-propanol to afford 4-(3-hydroxypropylthio)benzonitrile. 1.8g of 4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure T togive 4-(3-hydroxypropylthio)benzoic acid. 1.2 g of4-(3-hydroxypropylthio)benzoic acid was reacted via Procedure R to give4-(3-hydroxypropylsulfonyl)benzoic acid. 50 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(3-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product waspurified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide.MS (Q1) 431.3 (M)⁺.

Example 233N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-methoxyethylsulfonyl)benzamide

A mixture of 500 mg of methyl 4-mercaptobenzoate, 1.6 g of potassiumcarbonate, 1.2 g of 2-bromoethylmethylether and 329 mg oftetrabutylammonium iodide in 10 mL of acetone was refluxed for 16 h. Thereaction mixture was diluted with ethyl acetate, washed with H₂O andconcentrated. Purified by silica gel chromatography (0-50% ethylacetate/hexane) to yield 4-(2-methoxyethylthio)benzoate. 240 mg of4-(2-methoxyethylthio)benzoate was reacted via Procedure R to give4-(2-methoxyethylsulfonyl)benzoate. 120 mg of4-(2-methoxyethylsulfonyl)benzoate was hydrolyzed via Procedure M toyield 4-(2-methoxyethylsulfonyl)benzoic acid. 50 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(2-methoxyethylsulfonyl)benzoic acid via Procedure G. The product waspurified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-methoxyethylsulfonyl)benzamide.MS (Q1) 431.0 (M)⁺.

Example 234N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(propylsulfonyl)benzamide

1 g of 4-fluorobenzonitrile was used in Procedure Q with 1-propanethiolto afford 4-(propylthio)benzonitrile. 860 mg of4-(propylthio)benzonitrile was reacted via Procedure T to give4-(propylthio)benzoic acid. 700 mg of 4-(propylthio)benzoic acid wasreacted via Procedure R to give 4-(propylsulfonyl)benzoic acid. 60 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(propylsulfonyl)benzoic acid via Procedure G. The product was purifiedon reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(propylsulfonyl)benzamide. MS (Q1)415.0 (M)⁺.

Example 2352-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide

4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with2-mercaptoethanol to afford 2-chloro-4-(2-hydroxyethylthio)benzonitrile.1 g of 2-chloro-4-(2-hydroxyethylthio)benzonitrile was reacted viaProcedure T to give 2-chloro-4-(2-hydroxyethylthio)benzoic acid. 1 g of2-chloro-4-(2-hydroxyethylthio)benzoic acid was reacted via Procedure Rto yield 2-chloro-4-(2-hydroxyethylsulfonyl)benzoic acid. 50 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to2-chloro-4-(2-hydroxyethylsulfonyl)benzoic acid via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide.MS (Q1) 451.0 (M)⁺.

Example 2362-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide

4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with3-mercapto-1-propanol to afford2-chloro-4-(3-hydroxypropylthio)benzonitrile. 1 g of2-chloro-4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure Tto give 2-chloro-4-(3-hydroxypropylthio)benzoic acid. 1.2 g of2-chloro-4-(3-hydroxypropylthio)benzoic acid was reacted via Procedure Rto yield 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide.MS (Q1) 465.0 (M)⁺.

Example 2374-(allylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

7.3 g of 4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure Rto yield 4-(3-hydroxypropylsulfonyl)benzonitrile. 1.9 g of NBS was addedto a solution of 2 g of 4-(3-hydroxypropylsulfonyl)benzonitrile and 2.8g of triphenylphosphine in 10 mL of dichloromethane at 0° C. Thereaction mixture was stirred at 0˜5° C. for 1 h. The mixture was dilutedwith dichloromethane, washed with H₂O, dried (MgSO₄) and evaporated.Purified by silica gel chromatography (10-70% ethyl acetate/hexane) toafford 4-(3-bromopropylsulfonyl)benzonitrile. 300 mg of4-(3-bromopropylsulfonyl)benzonitrile was reacted via Procedure T togive 4-(allylsulfonyl)benzoic acid. 40 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(allylsulfonyl)benzoicacid via Procedure G. The product was purified on reverse phase HPLC toyield 4-(allylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS(Q1) 413.2 (M)⁺.

Example 2384-(allylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

115 mg of NBS was added to a solution of 200 mg of2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamideand 169 mg of triphenylphosphine in 3 mL of dichloromethane at 0° C. Thereaction mixture was stirred at 0˜5° C. for 1 h. The mixture was dilutedwith dichloromethane, washed with H₂O, dried (MgSO₄) and evaporated.Purified by prep TLC plate (60% ethyl acetate/hexane) to afford4-(3-bromopropylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.60 mg of4-(3-bromopropylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamideand 111 mg of cesium carbonate in 0.5 mL of DMF were heated to 100° C.in a sealed microwave reactor for 20 min. The reaction mixture wasevaporated, and the product was purified on reverse phase HPLC to yield4-(allylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 448.0 (M)⁺.

Example 2392-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-morpholinopropylsulfonyl)-benzamide

120 mg of4-(3-bromopropylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamidewas used in Procedure P with morpholine to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-morpholinopropylsulfonyl)benzamide.MS (Q1) 534.0 (M)⁺.

Example 2402-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopyrrolidin-1-yl)benzamide

A mixture of 500 mg of 2-chloro-4-florobenzonitrile, 821 mg of2-pyrrolidinone and 3 g of cesium carbonate in 5 mL of DMF was heated to100° C. in a sealed microwave reactor for 15 min. The reaction mixturewas diluted with ethyl acetate, washed with H₂O, dried (MgSO₄) andevaporated. Purified by silica gel chromatography (20-80% ethylacetate/hexane) to afford 2-chloro-4-(2-oxopyrrolidin-1-yl)benzonitrile.890 mg of 2-chloro-4-(2-oxopyrrolidin-1-yl)benzonitrile was reacted viaProcedure T to give 2-chloro-4-(2-oxopyrrolidin-1-yl)benzoic acid. 80 mgof 4-chloro-3-(pyridin-2-yl)aniline was coupled to2-chloro-4-(2-oxopyrrolidin-1-yl)benzoic acid via Procedure G. Theproduct was purified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopyrrolidin-1-yl)benzamide.MS (Q1) 426.2 (M)⁺.

Example 241N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxooxazolidin-3-yl)benzamide

A mixture of 1 g of methyl 4-iodobenzoate, 399 mg of 2-oxozolidone, 1.1g of potassium carbonate, 34 mg of N, N′-dimethylethylenediamine and 73mg of copper iodide in 10 mL of toluene was heated to 150° C. in asealed microwave reactor for 2 h. The reaction mixture was diluted withethyl acetate, washed with H₂O, dried (MgSO₄) and evaporated. Purifiedby silica gel chromatography (20-70% ethyl acetate/hexane) to affordmethyl 4-(2-oxooxazolidin-3-yl)benzoate. 530 mg of methyl4-(2-oxooxazolidin-3-yl)benzoate was hydrolyzed via Procedure M to give4-(2-oxooxazolidin-3-yl)benzoic acid. 70 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(2-oxooxazolidin-3-yl)benzoic acid via Procedure G. The product waspurified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxooxazolidin-3-yl)benzamide.MS (Q1) 394.2 (M)⁺.

Example 242N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)-2-methylbenzamide

4 g of 4-bromo-2-methylbenzonitrile was used in Procedure Q withethanethiol to afford 4-(ethylthio)-2-methylbenzonitrile. 2 g of4-(ethylthio)-2-methylbenzonitrile was reacted via Procedure R to give4-(ethylsulfonyl)-2-methylbenzonitrile. 2.5 g of4-(ethylsulfonyl)-2-methylbenzonitrile was reacted via Procedure T togive 4-(ethylsulfonyl)-2-methylbenzoic acid. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(ethylsulfonyl)-2-methylbenzoic acid via Procedure G. The product waspurified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)-2-methylbenzamide.MS (Q1) 415.0 (M)⁺.

Example 2432-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzamide

4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q withethanethiol to afford 2-chloro-4-(ethylthio)benzonitrile. 2 g of2-chloro-4-(ethylthio)benzonitrile was reacted via Procedure T to give2-chloro-4-(ethylthio)benzoic acid. 1.5 g of2-chloro-4-(ethylthio)benzoic acid was reacted via Procedure R to yield2-chloro-4-(ethylsulfonyl)benzoic acid. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to2-chloro-4-(ethylsulfonyl)benzoic acid via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzamide.MS (Q1) 435.1 (M)⁺.

Example 2442-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonyl)benzamide

2 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with2-propanethiol to afford 2-chloro-4-(isopropylthio)benzonitrile. 1.6 gof 2-chloro-4-(isopropythio)benzonitrile was reacted via Procedure T togive 2-chloro-4-(isopropylthio)benzoic acid. 1 g of2-chloro-4-(isopropylthio)benzoic acid was reacted via Procedure R togive 2-chloro-4-(isopropylsulfonyl)benzoic acid. 75 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to2-chloro-4-(isopropylsulfonyl)benzoic acid via Procedure G. The productwas purified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonyl)benzamide.MS (Q1) 449.1 (M)⁺.

Example 245N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonyl)benzamide

2 g of 4-fluorobenzonitrile was used in Procedure Q with 2-propanethiolto afford 4-(isopropylthio)benzonitrile. 900 mg of4-(isopropythio)benzonitrile was reacted via Procedure T to give4-(isopropylthio)benzoic acid. 730 mg of 4-(isopropylthio)benzoic acidwas reacted via Procedure R to give 4-(isopropylsulfonyl)benzoic acid.75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(isopropylsulfonyl)benzoic acid via Procedure G. The product waspurified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonyl)benzamide. MS(Q1) 415.0 (M)

Example 246N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonyl)benzamide

A solution of 500 mg of 4-bromo-2-methylbenzonitrile and 268 mg ofsodium thiomethoxide in 3 mL of DMF was stirred for 1 h. The reactionmixture was diluted with ethyl acetate, washed with H₂O, dried (MgSO₄)and evaporated to afford 2-methyl-4-(methylthio)benzonitrile. 400 mg of2-methyl-4-(methylthio)benzonitrile was reacted via Procedure T to give2-methyl-4-(methylthio)benzoic acid. 430 mg of2-methyl-4-(methylthio)benzoic acid was reacted via Procedure R to yield2-methyl-4-(methylsulfonyl)benzoic acid. 60 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to2-methyl-4-(methylsulfonyl)benzoic acid via Procedure G. The product waspurified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonyl)benzamide.MS (Q1) 401.0 (M)⁺.

Example 247N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(methylsulfonyl)nicotinamide

1 g of methyl 6-chloronicotinate was reacted via Procedure O to yieldmethyl 6-(methylsulfonyl)nicotinate. 1 g of methyl6-(methylsulfonyl)nicotinate was hydrolyzed via Procedure M to give6-(methylsulfonyl)nicotinic acid. 100 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to6-(methylsulfonyl)nicotinic acid via Procedure G. The product waspurified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(methylsulfonyl)nicotinamide. MS(Q1) 388.1 (M)⁺.

Example 248N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-phenylpyrimidine-5-carboxamide

50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to4-methyl-2-phenyl-5-pyrimidine carboxylic acid via Procedure G. Theproduct was purified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-phenylpyrimidine-5-carboxamide.MS (Q1) 401.1 (M)⁺.

Example 249N-(4-chloro-3-(pyridin-2-yl)phenyl)-1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide

50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid via ProcedureG. The product was purified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide.MS (Q1) 407.0 (M)⁺.

Example 250 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide

A mixture of 450 mg of 4-chloro-3-(pyridin-2-yl)aniline, 427 mg of6-chloronicotinyl chloride and 1.9 g of PS-DIEA in 10 mL ofdichloromethane was shook on the shaker for 3 h. The reaction mixturewas filtered and washed with dichloromethane. The filtrate wasconcentrated to yield6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide. MS (Q1) 344.2(M)⁺.

Example 251N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-ethylpiperazin-1-yl)nicotinamide

Procedure F was performed using 50 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 93 μL of1-ethylpiperazine in 0.5 mL of BuOH. Purified by reverse phase HPLC toyieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-ethylpiperazin-1-yl)nicotinamide.MS (Q1) 422.0 (M)⁺.

Example 252N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)nicotinamide

Procedure F was performed using 50 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 90 μL of1-(2-hydroxyethyl)piperazine in 0.5 mL of BuOH. Purified by reversephase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)nicotinamide.MS (Q1) 438.0 (M)⁺.

Example 253(R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)nicotinamide

Procedure F was performed using 50 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 57 μL ofR-1-Amino-2-propanol in 0.5 mL of BuOH. Purified by reverse phase HPLCto yield(R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)nicotinamide.MS (Q1) 383.4 (M)⁺.

Example 254(S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)nicotinamide

Procedure F was performed using 50 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 57 μL ofS-1-Amino-2-propanol in 0.5 mL of BuOH. Purified by reverse phase HPLCto yield(S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)nicotinamide.MS (Q1) 383.4 (M)⁺.

Example 255N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2,6-dimethylmorpholino)nicotinamide

Procedure F was performed using 50 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 90 μL of2,6-dimethylmorpholine in 0.5 mL of BuOH. Purified by reverse phase HPLCto yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2,6-dimethylmorpholino)nicotinamide.MS (Q1) 423.4 (M)⁺.

Example 256N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-hydroxypiperidin-1-yl)nicotinamide

Procedure F was performed using 50 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 74 mg of4-hydroxypiperidine in 0.5 mL of BuOH. Purified by reverse phase HPLC toyieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-hydroxypiperidin-1-yl)nicotinamide.MS (Q1) 409.3 (M)⁺.

Example 257N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)nicotinamide

21 mg of sodium hydride was added to a solution of 84 mg of3,5-dimethylpyrazole in 2 mL of DMF. The reaction mixture was stirredfor 10 min, and then added 100 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide. The reactionwas heated to 140° C. for 16 h. The mixture was quenched with MeOH andevaporated. The product was purified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)nicotinamide.MS (Q1) 404.3 (M)⁺.

Example 258N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-oxopiperidin-1-yl)nicotinamide

Procedure F was performed using 50 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 29 mg ofpiperazin-2-one in 0.5 mL of BuOH. Purified by reverse phase HPLC toyieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-oxopiperidin-1-yl)nicotinamide.MS (Q1) 408.3 (M)⁺.

Example 259N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopiperazin-1-yl)benzamide

A mixture of 1 g of methyl 4-iodobenzoate, 920 mg of 4-Boc-piperazinone,1.1 g of potassium carbonate, 32 mg of N, N′-dimethylethylenediamine and70 mg of copper iodide in 10 mL of toluene was heated to 150° C. in asealed microwave reactor for 3 h. The reaction mixture was diluted withethyl acetate, washed with H₂O, dried (MgSO₄) and evaporated. Purifiedby silica gel chromatography (20-80% ethyl acetate/hexane) to affordtert-butyl 4-(4-(methoxycarbonyl)phenyl)-3-oxopiperazine-1-carboxylate.500 mg of tert-butyl4-(4-(methoxycarbonyl)phenyl)-3-oxopiperazine-1-carboxylate washydrolyzed via Procedure M to give4-(4-(tert-buthoxycarbonyl)-2-oxopiperazin-1-yl)benzoic acid. 100 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to4-(4-(tert-buthoxycarbonyl)-2-oxopiperazin-1-yl)benzoic acid viaProcedure G. The reaction mixture was diluted with ethyl acetate, washedwith 0.1 N sodium hydroxide and brine, dried (MgSO₄) and evaporated toafford tert-butyl4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenyl)-3-oxopiperazine-1-carboxylate.300 mg of crude tert-butyl4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)phenyl)-3-oxopiperazine-1-carboxylatewas treated with TFA (2 mL) containing trace amounts of H₂O for 1 h. Thereaction mixture was evaporated and the crude product was purified byreverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopiperazin-1-yl)benzamide. MS(Q1) 407.3 (M)⁺.

Example 260N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-methyl-2-oxopiperazin-1-yl)benzamide

120 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopiperazin-1-yl)benzamide wasdissolved in 2 mL of DMF and then treated with 53 mg ofparaformaldehyde, 187 mg of sodium triacetoxyborohydride and 0.2 mL ofAcOH. After stirring 16 h, the reaction mixture was evaporated and thecrude product was purified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-methyl-2-oxopiperazin-1-yl)benzamide.MS (Q1) 421.3 (M)⁺.

Example 2612-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

2.2 g of methyl 4-(methylsulfonyl)-2-nitrobenzoate was reacted viaProcedure C to afford methyl 2-amino-4-(methylsulfonyl)benzoate. 500 mgof methyl 2-amino-4-(methylsulfonyl)benzoate was hydrolyzed viaProcedure M to give 2-amino-4-(methylsulfonyl)benzoic acid. 100 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to2-amino-4-(methylsulfonyl)benzoic acid via Procedure G. The product waspurified on reverse phase HPLC to yield2-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide.MS (Q1) 402.0 (M)⁺.

Example 2622-acetamido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

20 μL of acetyl chloride was added to a solution of 90 mg of2-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamidein 2 mL of pyridine at 0° C. The reaction mixture was allowed to warm toroom temperature and stirred for 2 h. The reaction was quenched withMeOH and evaporated. The product was purified on reverse phase HPLC toyield2-acetamido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide.MS (Q1) 444.0 (M)⁺.

Example 263N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-iodo-4-(methylsulfonyl)benzamide

600 mg of methyl 2-amino-4-(methylsulfonyl)benzoate was added to asolution of 4 mL of H₂O and 1 mL of concentrated sulfuric acid. Thesolution was cooled to 0° C. and a solution of 206 mg of sodium nitritein 1 mL of H₂O was added slowly. The reaction mixture was stirred for 2h and then a solution of 782 mg of potassium iodide in 2 mL of H₂O wasadded dropwise at 0° C. The reaction was allowed to warm to roomtemperature and stirred for 5 h. The mixture was extracted with ethylacetate. The combined organic extracts were washed with saturatedNa₂S₂O₃, dried (MgSO₄) and evaporated. Purified by silica gelchromatography (5-50% ethyl acetate/hexane) to afford methyl2-iodo-4-(methylsulfonyl)benzoate. 160 mg of methyl2-iodo-4-(methylsulfonyl)benzoate was hydrolyzed via Procedure M to give2-iodo-4-(methylsulfonyl)benzoic acid. 60 mg of4-chloro-3-(pyridin-2-yl)aniline was coupled to2-iodo-4-(methylsulfonyl)benzoic acid via Procedure G. The product waspurified on reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-iodo-4-(methylsulfonyl)benzamide.MS (Q1) 513.0 (M)⁺.

Example 264N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-methylnicotinamide

Stoichiometric amounts (0.04 mol) of methyl proplolate and ethyl3-aminocrotonate were heated to 140° C. for 1 h. 1 g of the crude(2E,4Z)-methyl-4-(1-aminoethylidene)-5-oxooct-2-enoate in 4 mL of DMFwas heated to 230° C. in a sealed microwave reactor for 40 min. Thereaction mixture was diluted with ethyl acetate, washed with H₂O, dried(MgSO₄) and evaporated to afford crude ethyl6-hydroxy-2-methylnicotinate. A mixture of 800 mg of crude ethyl6-hydroxy-2-methylnicotinate in 4 mL of phosphorus oxychloride washeated to 150° C. in a sealed microwave reactor for 15 min. The reactionmixture was poured into ice/water, extracted with diethyl ether. Thecombined organic layers were dried (MgSO₄) and evaporated. Purified bysilica gel chromatograph (0-20% ethyl acetate/hexane) to yield ethyl6-chloro-2-methylnicotinate. 400 mg of ethyl 6-chloro-2-methylnicotinatewas hydrolyzed via Procedure M to give 6-chloro-2-methylnicotinic acid.300 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to6-chloro-2-methylnicotinic acid via Procedure G. The reaction mixturewas diluted with ethyl acetate, washed with 0.1 N sodium hydroxide andbrine, dried (MgSO₄) and evaporated to afford6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide.Procedure F was performed using 100 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and128 mg of 2,6-dimethylpiperazine in 1 mL of BuOH. Purified by reversephase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-methylnicotinamide.MS (Q1) 436.3 (M)⁺.

Example 265(S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methylpiperazin-1-yl)nicotinamide

Procedure F was performed using 100 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and112 mg of S-(−)-2-methylpiperizine in 1 mL of BuOH. Purified by reversephase HPLC to yield(S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methylpiperazin-1-yl)nicotinamide.MS (Q1) 422.3 (M)⁺.

Example 266(R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methylpiperazin-1-yl)nicotinamide

Procedure F was performed using 100 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and112 mg of R-(+)-2-methylpiperizine in 1 mL of BuOH. Purified by reversephase HPLC to yield(R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methylpiperazin-1-yl)nicotinamide.MS (Q1) 422.3 (M)⁺.

Example 267N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methylpiperazin-1-yl)nicotinamide

Procedure F was performed using 100 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and112 mg of 2-methylpiperizine in 1 mL of BuOH. Purified by reverse phaseHPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methylpiperazin-1-yl)nicotinamide.MS (Q1) 422.3 (M)⁺.

Example 268N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-(2-hydroxyacetyl)piperazin-1-yl)-2-methylnicotinamide

100 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(piperazin-1-yl)nicotinamidewas coupled to glycolic acid via Procedure G. The product was purifiedon reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-(2-hydroxyacetyl)piperazin-1-yl)-2-methylnicotinamide.MS (Q1) 466.3 (M)⁺.

Example 269N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(4-(methylsulfonyl)piperazin-1-yl)nicotinamide

1.3 mL of methanesulfonyl chloride was slowly added to a solution of 2 gof 1-Boc-piperazine and 1.3 mL of pyridine in 6 mL of dichloromethane at0° C. The reaction mixture was allowed to warm to room temperature andstirred for 2 h while being monitored by TLC. Upon completion, themixture was diluted with dichloromethane, washed with H₂O, dried (MgSO₄)and evaporated. Purified by silica gel chromatograph (20-100% ethylacetate/hexane) to affordtert-butyl-4-(methylsulfonyl)piperazine-1-carboxylate. 930 mg oftert-butyl-4-(methylsulfonyl)piperazine-1-carboxylate was treated with4N HCl in dioxane for 2 h. The reaction mixture was evaporated to givethe HCl salt of 1-(methylsulfonyl)piperazine. Procedure F was performedusing 50 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide, 69 mgof 1-(methylsulfonyl)piperazine and DIEPA (1 eq) in 0.5 mL of BuOH.Purified by reverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(4-(methylsulfonyl)piperazin-1-yl)nicotinamide.MS (Q1) 486.3 (M)⁺.

Example 270N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-thiomorpholinonicotinamide

Procedure F was performed using 90 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 78μL of thiomorpholine in 1 mL of BuOH. Purified by reverse phase HPLC toyieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-thiomorpholinonicotinamide.MS (Q1) 425.3 (M)⁺.

Example 271N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-sulfonylmorpholinonicotinamide

100 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-thiomorpholinonicotinamidewas reacted via produce R. The product was purified on reverse phaseHPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-sulfonylmorpholinonicotinamide.MS (Q1) 457.3 (M)⁺.

Example 272N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(2-(pyrrolidin-1-yl)ethylamino)-nicotinamide

Procedure F was performed using 100 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 70μL of 1-(2-aminoethyl)pyrrolidine in 1 mL of BuOH. Purified by reversephase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(2-(pyrrolidin-1-yl)ethylamino)nicotinamide.MS (Q1) 436.0 (M)⁺.

Example 273N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methylnicotinamide

Procedure F was performed using 60 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 66μL of N,N,N′-trimethylethylenediamine in 0.5 mL of BuOH. Purified byreverse phase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methylnicotinamide.MS (Q1) 424.0 (M)⁺.

Example 274N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-oxopiperazin-1-yl)nicotinamide

Procedure F was performed using 100 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 84mg of piperazine-2-one in 1 mL of BuOH. Purified by reverse phase HPLCto yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-oxopiperazin-1-yl)nicotinamide.MS (Q1) 422.3 (M)⁺.

Example 275N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methyl-1H-1,2,4-triazol-1-yl)nicotinamide

A mixture of 57 mg of 3-methyl-1,2,4-triazol and 16 mg of sodium hydridein 2 mL of DMF was stirred for 10 min. 80 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide wasadded. The reaction was heated to 140° C. for 16 h. The reaction mixturewas quenched with MeOH and evaporated. Purified by reverse phase HPLC toyieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methyl-1H-1,2,4-triazol-1-yl)nicotinamide.MS (Q1) 405.3 (M)⁺.

Example 276N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(1H-1,2,4-triazol-1-yl)nicotinamide

A mixture of 41 mg of 1,2,4-triazol and 14 mg of sodium hydride in 2 mLof DMF was stirred for 10 min. 70 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide wasadded. The reaction was heated to 140° C. for 6 h. The reaction mixturewas quenched with MeOH and evaporated. Purified by reverse phase HPLC toyieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(1H-1,2,4-triazol-1-yl)nicotinamide.MS (Q1) 391.4 (M)⁺.

Example 277N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(1H-pyrazol-1-yl)nicotinamide

A mixture of 52 mg of pyrazole and 18 mg of sodium hydride in 2 mL ofDMF were stirred for 10 min. 90 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide wasadded.

The reaction was heated to 140° C. for 5 h. The reaction mixture wasquenched with MeOH and evaporated. Purified by reverse phase HPLC toyieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(1H-pyrazol-1-yl)nicotinamide.MS (Q1) 390.0 (M)⁺.

Example 278N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(piperazin-1-yl)nicotinamide

Procedure F was performed using 80 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and209 mg of 1-Boc-piperizine in 1 mL of BuOH. The reaction mixture wasevaporated to afford tert-butyl4-(5-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)-6-methylpyridin-2-yl)piperazine-1-carboxylate.150 mg of tert-butyl4-(5-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)-6-methylpyridin-2-yl)piperazine-1-carboxylatewas treated with TFA (1 mL) containing trace amounts of H₂O for 2 h. Thereaction mixture was diluted with ethyl acetate, washed with 0.1N sodiumhydroxide and brine, dried (MgSO₄) and evaporated. Purified by reversephase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(piperazin-1-yl)nicotinamide.MS (Q1) 408.3 (M)⁺.

Example 279(R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)-2-methylnicotinamide

Procedure F was performed using 60 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and116 μL of R-(−)-1-amino-2-propanol in 0.5 mL of BuOH. Purified byreverse phase HPLC to yield(R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)-2-methylnicotinamide.MS (Q1) 397.4 (M)⁺.

Example 280(S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)-2-methylnicotinamide

Procedure F was performed using 60 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and116 μL of S-(+)-1-amino-2-propanol in 0.5 mL of BuOH. Purified byreverse phase HPLC to yield(S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)-2-methylnicotinamide.MS (Q1) 397.4 (M)⁺.

Example 2816-(2-(1H-imidazol-4-yl)ethylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide

Procedure F was performed using 60 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 93mg of histamine in 0.5 mL of BuOH. Purified by reverse phase HPLC toyield6-(2-(1H-imidazol-4-yl)ethylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide.MS (Q1) 433.0 (M)

Example 2826-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide

Procedure F was performed using 55 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 99mg of 1-acetylpiperazine in 0.5 mL of BuOH. Purified by reverse phaseHPLC to yield6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide.MS (Q1) 450.4 (M)⁺.

Example 283N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2,6-dimethylmorpholino)-2-methylnicotinamide

Procedure F was performed using 55 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 95mg of 2,6-dimethylmorpholine in 0.5 mL of BuOH. Purified by reversephase HPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2,6-dimethylmorpholino)-2-methylnicotinamide.MS (Q1) 436.2 (M)⁺.

Example 284N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-hydroxypiperidin-1-yl)-2-methylnicotinamide

Procedure F was performed using 55 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 78mg of 4-hydropiperidine in 0.5 mL of BuOH. Purified by reverse phaseHPLC to yieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-hydroxypiperidin-1-yl)-2-methylnicotinamide.MS (Q1) 422.1 (M)⁺.

Example 2856-(3-(1H-imidazol-1-yl)propylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide

Procedure F was performed using 55 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 92μL of 1-(3-aminopropyl)-imidazole in 0.5 mL of BuOH. Purified by reversephase HPLC to yield6-(3-(1H-imidazol-1-yl)propylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide.MS (Q1) 446.1 (M)⁺.

Example 286N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(isobutylamino)-2-methylnicotinamide

Procedure F was performed using 50 mg of6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 70μL of isobutylamine in 0.5 mL of BuOH. Purified by reverse phase HPLC toyieldN-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(isobutylamino)-2-methylnicotinamide.MS (Q1) 395.4 (M)⁺.

Example 2872-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴,N⁴-dimethylterephthalamide

290 mg of dimethylamine hydrochloride was coupled to 1 g of4-(tert-butoxycarbonyl)-3-chlorobenzoic acid via Procedure G. Thereaction mixture was diluted with ethyl acetate, washed with 0.1 N HCl,0.1 N NaOH and brine, dried (MgSO₄) and evaporated to afford tert-butyl2-chloro-4-(dimethylcarbamoyl)benzoate. 1.1 g of tert-butyl2-chloro-4-(dimethylcarbamoyl)benzoate was treated with TFA (4 mL)containing trace amounts of H₂O for 2 h. The reaction mixture wasevaporated, and then added 0.1 N HCl. The resulting solid was filteredand washed with H₂O to yield 2-chloro-4-(dimethylcarbamoyl)benzoic acid.100 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to2-chloro-4-(dimethylcarbamoyl)benzoic acid via Procedure G. The productwas purified on reverse phase HPLC to yield2-chloro-N¹-(4-chloro-3-(pyridin-2-yl)phenyl)-N⁴,N⁴-dimethylterephthalamide.

MS (Q1) 414.1 (M)⁺.

Example 288N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(morpholine-4-carbonyl)nicotinamide

63 mg of morpholine was coupled to 120 mg of5-(methoxycarbonyl)pyridine-2-carboxylic acid via Procedure G. Thereaction mixture was diluted with ethyl acetate, washed with saturatedsodium bicarbonate and brine, dried (MgSO₄) and evaporated to affordmethyl 6-(morpholine-4-carbonyl)nicotinate. 180 mg of methyl6-(morpholine-4-carbonyl)nicotinate was hydrolyzed via Procedure M togive 6-(morpholine-4-carbonyl)nicotinic acid. 100 mg of4-chloro-3-(pyridine-2-yl)aniline was coupled to6-(morpholine-4-carbonyl)nicotinic acid via Procedure G. The product waspurified on reverse phase HPLC to yield2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(morpholine-4-carbonyl)nicotinamide.MS (Q1) 423.4 (M)⁺.

Example 289N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide

3-Hydroxy-4-methylbenzoic acid (6.86 g, 45.1 mmol) was dissolved inmethanol (200 ml). 4N HCl in 1,4-dioxane (34 ml, 0.135 mmol HCl) wasadded and the solution heated to 55° C. for 18 hours. The solvent wasconcentrated on a rotary evaporator, and then partitioned between waterand ethyl acetate. The aqueous portion was extracted with ethyl acetateonce, and the ethyl acetate extracts were combined and washed with wateronce, brine once, dried with MgSO₄, and evaporated to methyl3-hydroxy-4-methylbenzoate as a crude tan solid (6.66 g) which was usedwithout purification. Methyl 3-hydroxy-4-methylbenzoate (6.66 g, 40.1mmol) was dissolved in dichloromethane (200 ml), treated with pyridine(4.3 ml, 60.2 mmol), and cooled in an ice water bath. Acetyl chloride(3.6 ml, 50.1 mmol) was added dropwise. The solution was allowed to warmto room temperature, with stirring, over 18 hours. The solution waswashed with 1 N aqueous HCl twice, water once, brine once, dried withMgSO₄, and evaporated to methyl 3-acetoxy-4-methylbenzoate as a crudetan oil (6.93 g) which was used without purification. Methyl3-acetoxy-4-methylbenzoate (6.38 g, 30.6 mmol) was dissolved in carbontetrachloride (130 ml) and treated with benzoic peroxyanhydride (200 mg,0.83 mmol) and NBS (5.45 g, 30.6 mmol), then heated to 85° C. for 3hours. After cooling to room temperature, the solution was filteredthrough Celite 545 and evaporated to a crude yellow solid which waspurified by silica gel flash chromatography (5% dichloromethane/hexanesincreasing to 35% dichloromethane/hexanes) to yield methyl3-acetoxy-4-(bromomethyl)benzoate as an off white solid (4.18 g). Methyl3-acetoxy-4-(bromomethyl)benzoate (2.00 g, 6.97 mmol) was used inprocedure O to afford methyl 3-acetoxy-4-(methylsulfonylmethyl)benzoateas a white solid (1.67 g) which was used without purification. Methyl3-acetoxy-4-(methylsulfonylmethyl)benzoate (1.67 g, 5.83 mmol) wassaponified via procedure M to afford3-hydroxy-4-(methylsulfonylmethyl)benzoic acid as a white solid (1.05 g)which was used without purification.3-Hydroxy-4-(methylsulfonylmethyl)benzoic acid (860 mg, 3.74 mmol) wasdissolved in 1,4-dioxane (25 ml) and treated with thionyl chloride (8ml) and DMF (5 drops), then heated to 50° C. for 2 hours. The reactionwas cooled and evaporated to an oil. The oil residue was dissolved indichloromethane (40 ml), cooled in an ice water bath, and treateddropwise with a solution of 4-chloro-3-(pyridin-2-yl)aniline (767 mg,3.74 mmol) in dichloromethane (30 ml). The reaction was stirred 18hours, allowing to warm to room temperature. The reaction was dilutedwith dichloromethane (40 ml) and stirred vigorously with water (50 ml)while acidifying to pH 6 with 1 M citric acid. The dichloromethaneportion was separated, and enough methanol was added to dissolveprecipitating solids. The solution was washed with water once, brineonce, dried with MgSO₄, and evaporated to a solid which was trituratedwith dichloromethane, filtered, and air dried to yield 909 mg of crudeproduct. A portion (20 mg) was purified on reverse phase HPLC to yield16 mg of purifiedN-(4-chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamideas a white solid. MS (Q1) 417 (M)⁺.

Example 290N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-isobutoxy-4-(methylsulfonylmethyl)benzamide

N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide(50 mg, 0.12 mmol) was treated with 1-bromo-2-methylpropane (26 μl, 0.24mmol) via procedure U to yield 19 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-3-isobutoxy-4-(methylsulfonylmethyl)benzamide.MS (Q1) 473 (M)⁺.

Example 291N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-methoxy-4-(methylsulfonylmethyl)benzamide

N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide(50 mg, 0.12 mmol) was treated with iodomethane (7.5 μl, 0.12 mmol) viaprocedure U to yield 12 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-3-methoxy-4-(methylsulfonylmethyl)benzamide.MS (Q1) 431 (M)⁺.

Example 292N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-ethoxy-4-(methylsulfonylmethyl)benzamide

N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide(50 mg, 0.12 mmol) was treated with iodoethane (10 μl, 0.12 mmol) viaprocedure U to yield 22 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-3-ethoxy-4-(methylsulfonylmethyl)benzamide.MS (Q1) 445 (M)⁺.

Example 293N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)-4-(methylsulfonylmethyl)benzamide

N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide(1.00 g, 2.40 mmol) was dissolved in DMF (20 ml). Cesium carbonate (1.56g, 4.8 mmol) and 1,2-dibromoethane (0.83 ml, 9.6 mmol) were added, andthe reaction was stirred at 50° C. for 18 hours. The reaction wasquenched with water, basified with 10% aqueous NaOH, and extracted withethyl acetate twice. The ethyl extracts were washed with water once,brine once, dried with MgSO₄, and evaporated to a crude oil which waspurified by chromatography (25% hexanes in ethyl acetate) to yield 490mg of3-(2-bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamideas a yellow solid.3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide(100 mg, 0.19 mmol) was dissolved in DMF (2.0 ml), and potassiumcarbonate (32 mg, 0.23 mmol) and tert-butyl piperazine-1-carboxylate (38mg, 0.21 mmol) were added. The reaction was stirred for 18 hours at roomtemperature, quenched in water, and extracted with ethyl acetate twice.The ethyl acetate extracts were washed with water once, brine once,dried with MgSO₄, and evaporated to a crude oil. The oil was dissolvedin dichloromethane (1 ml) and treated with trifluoroacetic acid (3 ml)for 1 hour. The reaction was evaporated to dryness, and the crude solidwas purified on reverse phase HPLC to yield 63 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(piperazin-1-yl)ethoxy)benzamideas a white solid.N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(piperazin-1-yl)ethoxy)benzamide(30 mg, 0.047 mmol) was dissolved in dichloromethane (1.5 ml) and THF(1.0 ml). N-ethyl-N-isopropylpropan-2-amine (18 μl, 0.10 mmol) andmethanesulfonyl chloride (4 μl, 0.051 mmol) were added, and the reactionstirred at room temperature for 72 hours. AdditionalN-ethyl-N-isopropylpropan-2-amine (9 μl, 0.051 mmol) and methanesulfonylchloride (4 μl, 0.051 mmol) were added and the reaction stirred for 2hours. After a further addition of methanesulfonyl chloride (4 μl, 0.051mmol), the reaction was stirred for 2 hours and evaporated to a crudesolid which was purified on reverse phase HPLC to yield 8 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)-4-(methylsulfonylmethyl)benzamide.MS (Q1) 607 (M)⁺.

Example 294N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(3-oxopiperazin-1-yl)ethoxy)benzamide

3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide(50 mg, 0.095 mmol) was dissolved in DMF (1.0 ml) and treated withpotassium carbonate (18 mg, 0.13 mmol) and piperazin-2-one (11 mg, 0.11mmol) for 18 hours. The reaction was heated for 2.0 hours at 50° C.,then additional potassium carbonate (18 mg, 0.13 mmol) andpiperazin-2-one (11 mg, 0.11 mmol) was added. After 2 hours, thereaction was quenched in 5% NaOH and extracted with ethyl acetate twice.The ethyl acetate extracts were washed with water once, brine once,dried with MgSO₄, and purified by reverse phase HPLC to yield 16 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(3-oxopiperazin-1-yl)ethoxy)benzamide.MS (Q1) 558 (M)⁺.

Example 2953-(2-(4-Acetylpiperazin-1-yl)ethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide

3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide(50 mg, 0.095 mmol) was dissolved in DMF (1.0 ml) and treated withpotassium carbonate (18 mg, 0.13 mmol) and 1-(piperazin-1-yl)ethanone(15 mg, 0.11 mmol) for 18 hours. The reaction was heated for 2.0 hoursat 50° C., then additional potassium carbonate (18 mg, 0.13 mmol) and1-(piperazin-1-yl)ethanone (15 mg, 0.11 mmol) was added. After 2 hours,the reaction was quenched in 5% NaOH and extracted with ethyl acetatetwice. The ethyl acetate extracts were washed with water once, brineonce, dried with MgSO₄, and purified by reverse phase HPLC to yield 18mg of3-(2-(4-acetylpiperazin-1-yl)ethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide.MS (Q1) 543 (M)⁺.

Example 296N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-(2-(2,6-dimethylmorpholino)ethoxy)-4-(methylsulfonylmethyl)benzamide

3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide(50 mg, 0.095 mmol) was dissolved in DMF (1.0 ml) and treated withpotassium carbonate (18 mg, 0.13 mmol) and 2,6-dimethylmorpholine (14μl, 0.11 mmol), and stirred at room temperature for 18 hours. Thereaction was quenched in 5% NaOH and extracted with ethyl acetate twice.The ethyl acetate extracts were washed with water once, brine once,dried with MgSO₄, and purified by reverse phase HPLC to yield 20 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(2-(2,6-dimethylmorpholino)ethoxy)-4-(methylsulfonylmethyl)benzamide.MS (Q1) 571 (M)⁺.

Example 297N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-morpholinoethoxy)benzamide

3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide(50 mg, 0.095 mmol) was dissolved in acetonitrile (1.0 ml) and DMF (1.0ml), treated with potassium carbonate (16 mg, 0.12 mmol) and morpholine(10 μl, 0.11 mmol), and stirred 18 hours at room temperature. Thereaction was heated to 50° C. for 8 hours, and then was allowed to stir18 hours at room temperature. The reaction was quenched in water andextracted with ethyl acetate twice. The ethyl acetate extracts werewashed with water once, brine once, dried with MgSO₄, and evaporated toan oil which was purified by reverse phase HPLC to yield 30 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-morpholinoethoxy)benzamide.MS (Q1) 530 (M)⁺.

Example 298N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(piperidin-1-yl)ethoxy)benzamide

3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide(50 mg, 0.095 mmol) was dissolved in dichloromethane (1.0 ml), treatedwith triethylamine (20 μl, 0.15 mmol) and piperidine (11 μl, 0.11 mmol),and stirred 2.0 hours at room temperature.

Acetonitrile (0.25 ml) and N-ethyl-N-isopropylpropan-2-amine (25 μl,0.19 mmol) were added, and the reaction was stirred for an additional 45hours. The reaction was quenched in water and extracted withdichloromethane twice. The dichloromethane extracts were washed withwater once, brine once, dried with MgSO₄, and evaporated to an solidwhich was purified by reverse phase HPLC to yield 17 mgN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(piperidin-1-yl)ethoxy)benzamide.MS (Q1) 528 (M)⁺.

Example 299N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(pyrrolidin-1-yl)ethoxy)benzamide

3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide(40 mg, 0.076 mmol) was dissolved in acetonitrile (1.0 ml) and DMF (1.0ml), treated with potassium carbonate (16 mg, 0.12 mmol) and pyrrolidine(7 μl, 0.084 mmol), and stirred 18 hours at room temperature. Thereaction was quenched in water and extracted with ethyl acetate twice.The ethyl acetate extracts were washed with water once, brine once,dried with MgSO₄, and evaporated to an oil which was purified by reversephase HPLC to yield 30 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(pyrrolidin-1-yl)ethoxy)benzamide.MS (Q1) 514 (M)⁺.

Example 3003-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide

4-(Bromomethyl)-3-nitrobenzoic acid (2.00 g, 7.69 mmol) was dissolved inmethanol (20 ml) and treated with 1 drop of concentrated sulfuric acid,then stirred 72 hours at room temperature. An additional 3 drops ofconcentrated sulfuric acid was added, and the reaction stirred at 50° C.for 24 hours. The solvent was concentrated on a rotary evaporator,diluted with ethyl acetate, and washed with water twice, saturatedNaHCO₃ once, water once, brine once, dried with MgSO₄, and evaporated toa 1.82 g of a yellow oil, methyl 4-(bromomethyl)-3-nitrobenzoate andused without purification. Methyl 4-(bromomethyl)-3-nitrobenzoate (1.82g, 6.64 mmol) was used in procedure O to afford 1.66 g of methyl4-(methylsulfonylmethyl)-3-nitrobenzoate as a solid which was usedwithout purification. Methyl 4-(methylsulfonylmethyl)-3-nitrobenzoate(1.66 g, 6.07 mmol) was saponified via procedure M to afford 1.21 g of4-(methylsulfonylmethyl)-3-nitrobenzoic acid as an orange solid, whichwas used without purification. 4-(Methylsulfonylmethyl)-3-nitrobenzoicacid (639 mg, 2.46 mmol) was dissolved in 1,4-dioxane (15 ml), treatedwith thionyl chloride (1.0 ml) and DMF (1 drop), and stirred at roomtemperature for 18 hours, then at 50° C. for 8 hours, then at roomtemperature for 18 hours. After an additional 4.0 hours at 50° C., thesolvents and excess thionyl chloride were removed via rotary evaporator,and the residue was dissolved dichloromethane (25.0 ml) and treated withN-ethyl-N-isopropylpropan-2-amine (1.7 ml, 9.8 mmol) and4-chloro-3-(pyridin-2-yl)aniline (503 mg, 2.46 mmol) and stirred for 20min at room temperature, over which time a solid precipitated. Water wasadded, and the mixture was filtered and air dried, to afford 797 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-nitrobenzamideas a tan-yellow solid.N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-nitrobenzamide(786 mg, 1.76 mmol) was dissolved in ethanol (74 ml) and concentratedHCl (12 ml). Tin(II) chloride dihydrate (1.31 g, 5.82 mmol) was addedand the reaction was heated to 55° C. for 2.5 hours. The reaction wascooled in an ice bath and triethylamine (10 ml) was added to basify thesolution. The reaction was evaporated to a yellow solid which wasslurried in ethyl acetate. The slurry was filtered through Celite 545,and the mother liquors were washed with water twice, brine once, driedwith MgSO₄, and evaporated to 552 mg of as a crude yellow solid, 20 mgof which was purified by reverse phase HPLC to afford 13 mg of purified3-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide.MS (Q1) 416 (M)⁺.

Example 3013-Acetamido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide

3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide(30 mg, 0.072 mmol) was reacted with acetyl chloride (5.6 μl, 0.079 mol)via procedure V to afford 19 mg of3-acetamido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamideas a white solid. MS (Q1) 458 (M)⁺.

Example 302 N-(5-(4-Chloro-3-(pyridin-2-yl)phenylcarbamoyl)-2-(methylsulfonylmethyl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide

3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide(30 mg, 0.072 mmol) was reacted with2-methyl-6-(trifluoromethyl)nicotinoyl chloride (19 mg, 0.079 mmol) viaprocedure V to afford 16 mg ofN-(5-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)-2-(methylsulfonylmethyl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamideas a white solid. MS (Q1) 603 (M)⁺.

Example 3033-Benzamido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide

3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide(30 mg, 0.072 mmol) was reacted with benzoyl chloride (9 μl, 0.079 mmol)via procedure V to afford 17 mg of3-benzamido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamideas a white solid. MS (Q1) 520 (M)⁺.

Example 304N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(pyrrolidin-1-yl)acetamido)benzamide

3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide(100 mg, 0.24 mmol) was dissolved in 1,4-dioxane (5.0 ml), treated withtriethylamine (274 μl, 1.97 mmol) and 2-bromoacetyl bromide (121 μl,1.39 mmol). The reaction was heated to reflux for 10 minutes, andstirred at room temperature for 18 hours. The reaction was quenched withwater, and extracted twice with ethyl acetate. The ethyl acetateextracts were filtered, washed with water once, brine once, dried withMgSO₄, evaporated to 158 mg of a crude brown oil,3-(2-bromoacetamido)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide,which was used without further purification. Crude3-(2-bromoacetamido)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl-methyl)benzamide(158 mg) was dissolved in DMF, treated withN-ethyl-N-isopropylpropan-2-amine (61 μl, 0.35 mmol) and pyrrolidine (27μl, 0.32 mmol), and stirred at room temperature for 18 hours. Thereaction was quenched with water and extracted with ethyl acetate twice.The ethyl acetate extracts were washed with water once, brine once,dried with MgSO₄, evaporated to a tan solid which was purified byreverse phase HPLC to afford 27 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(pyrrolidin-1-yl)acetamido)benzamideas a white powder. MS (Q1) 527 (M)⁺.

Example 3054-(N-(3-(1H-Imidazol-4-yl)propyl)carbamimidoyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

4-Chloro-3-(pyridin-2-yl)aniline (687 mg, 3.36 mmol) was dissolved indichloromethane (8.0 ml) and THF (8.0 ml), treated with pyridine (0.33ml, 4.0 mmol), and cooled to 0° C. 4-Cyanobenzoyl chloride (612 mg, 3.7mmol) was added and the reaction was stirred for 1.0 hour. The reactionwas diluted with dichloromethane and methanol was added to dissolve allsolids. The solution was washed with water once, brine once, dried withMgSO₄, and evaporated to an orange solid which was purified by silicagel flash column chromatography (50% ethyl acetate/50% hexanes) toafford 908 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide asa yellow solid. N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide(500 mg, 1.5 mmol) was slurried in ethanol (75 ml) and heated until justdissolved. The solution was cooled in an ice bath, and saturated withHCl gas. The solution was heated briefly to 70° C. to dissolveprecipitated solids, cooled in an ice bath, and resaturated with HClgas. The solution was then stored at 0° C. for 18 hours. The solutionwas saturated again with HCl gas, heated to 70° C. until all solidsdissolved, cooled to 0° C., resaturated with HCl gas, and stored at 0°C. for 18 hours. Finally, nitrogen gas was bubbled through the solutionfor 1.0 hour, and the solution was evaporated to dryness. The residuewas dissolved in methanol, treated with MP-carbonate (2.57 g) andstirred 30 min. The solution was filtered to afford a neutral,methanolic solution of ethyl4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate, which wasdiluted with enough methanol to make a 0.075 M solution.

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml ofa 0.075 M methanol solution, 0.15 mmol) was treated with3-(1H-imidazol-4-yl)propan-1-amine (27 μl, 0.23 mmol) via procedure W toafford 83 mg of4-(N-(3-(1H-imidazol-4-yl)propyl)carbamimidoyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 459 (M)⁺.

Example 306N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-(pyrrolidin-2-yl)ethyl)carbamimidoyl)benzamide

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml ofa 0.075 M methanol solution, 0.15 mmol) was treated with2-(pyrrolidin-2-yl)ethanamine (28 μl, 0.23 mmol) via procedure W toafford 90 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-(pyrrolidin-2-yl)ethyl)carbamimidoyl)benzamide.MS (Q1) 448 (M)⁺.

Example 307N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-((tetrahydrofuran-2-yl)methyl)carbamimidoyl)benzamide

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml ofa 0.075 M methanol solution, 0.15 mmol) was treated with(tetrahydrofuran-2-yl)methanamine (23 μl, 0.23 mmol) via procedure W toafford 76 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-((tetrahydrofuran-2-yl)methyl)carbamimidoyl)benzamide.MS (Q1) 435 (M)⁺.

Example 3084-(N-(2-(1H-Imidazol-4-yl)ethyl)carbamimidoyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml ofa 0.075 M methanol solution, 0.15 mmol) was treated with2-(1H-imidazol-4-yl)ethanamine (25 mg, 0.23 mmol) via procedure W toafford 90 mg of4-(N-(2-(1H-imidazol-4-yl)ethyl)carbamimidoyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.MS (Q1) 445 (M)⁺.

Example 309N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2,2,2-trifluoroethyl)carbamimidoyl)benzamide

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml ofa 0.075 M methanol solution, 0.15 mmol) was treated with2,2,2-trifluoroethanamine (18 μl, 0.23 mmol) via procedure W to afford56 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2,2,2-trifluoroethyl)carbamimidoyl)benzamide.MS (Q1) 433 (M)⁺.

Example 310N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-((2,6-dimethylmorpholino)(imino)methyl)-benzamide

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml ofa 0.075 M methanol solution, 0.15 mmol) was treated with2,6-dimethylmorpholine (28 μl, 0.23 mmol) via procedure W to afford 74mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,6-dimethylmorpholino)(imino)methyl)-benzamide.MS (Q1) 449 (M)⁺.

Example 311N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-(3-methoxypropyl)carbamimidoyl)-benzamide

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml ofa 0.075 M methanol solution, 0.15 mmol) was treated with3-methoxypropan-1-amine (23 μl, 0.23 mmol) via procedure W to afford 68mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(3-methoxypropyl)carbamimidoyl)-benzamide.MS (Q1) 423 (M)⁺.

Example 312N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)carbamimidoyl)benzamide

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml ofa 0.075 M methanol solution, 0.15 mmol) was treated with2-methoxyethanamine (19 μl, 0.23 mmol) via procedure W to afford 50 mgofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)carbamimidoyl)benzamide.MS (Q1) 409 (M)⁺.

Example 313N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-cyclohexylcarbamimidoyl)benzamide

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml ofa 0.075 M methanol solution, 0.15 mmol) was treated with cyclohexanamine(26 μl, 0.23 mmol) via procedure W to afford 30 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-cyclohexylcarbamimidoyl)benzamide.MS (Q1) 433 (M)⁺.

Example 314N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(imino(4-methylpiperazin-1-yl)methyl)benzamide

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml ofa 0.075 M methanol solution, 0.15 mmol) was treated with1-methylpiperazine (23 mg, 0.23 mmol) via procedure W to afford 35 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(imino(4-methylpiperazin-1-yl)methyl)benzamide.MS (Q1) 434 (M)⁺.

Example 315N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-propylcarbamimidoyl)benzamide

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml ofa 0.075 M methanol solution, 0.15 mmol) was treated with propan-1-amine(18 μl, 0.23 mmol) via procedure W to afford 39 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-propylcarbamimidoyl)benzamide.MS (Q1) 393 (M)⁺.

Example 316N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(imino(pyrrolidin-1-yl)methyl)benzamide

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml ofa 0.075 M methanol solution, 0.15 mmol) was treated with pyrrolidine (19μl, 0.23 mmol) via procedure W to afford 25 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(imino(pyrrolidin-1-yl)methyl)benzamide.MS (Q1) 405 (M)⁺.

Example 317N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-phenylcarbamimidoyl)benzamide

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml ofa 0.075 M methanol solution, 0.15 mmol) was treated with aniline (21 μl,0.23 mmol) via procedure W to afford 7 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-phenylcarbamimidoyl)benzamide.MS (Q1) 427 (M)⁺.

Example 318N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(imino(morpholino)methyl)benzamide

N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide (300 mg, 0.899mmol) was slurried in 45 ml ethanol and treated with 10 ml of ethanolsaturated with HCl. The reaction was stored at 0° C. for 3 days, thenheated to 75° C. for 3.0 hours, and cooled to room temperature for 18hours. The reaction was cooled in an ice bath, and saturated with HClgas. After storing at 0° C. for an additional 3 days, N₂ gas was bubbledthrough the solution for 1.0 hour, and the solution was diluted withenough ethanol to make a 0.0155 M solution of ethyl4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate. Ethyl4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (17.5 ml of a0.0155 M ethanol solution, 0.27 mmol) was treated with morpholine (1.0ml, 11.4 mmol) for 3 days. The ethanol was evaporated, and the residuepurified by reverse phase HPLC to afford 30 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(imino(morpholino)methyl)benzamide.MS (Q1) 421 (M)⁺.

Example 319N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(imino(piperidin-1-yl)methyl)benzamide

Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (17.5 mlof a 0.0155 M solution, 0.27 mmol) was treated with piperidine (1.0 ml,10.0 mmol) for 3 days. The ethanol was evaporated, and the residuepurified by reverse phase HPLC to afford 26 mg ofN-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(imino(piperidin-1-yl)methyl)benzamide.MS (Q1) 419 (M)⁺.

Example 320 Hedgehog Signalling Inhibition Assays

Mouse Reporter Cell lines—10T1/2-GliLuc [S12] cells (derived from cellline C3H10T1/2 ATCC # CCL-226); Mouse Embryonic Fibroblasts); GrowthMedium: Dulbecco's modified Eagles' Medium (DMEM) supplemented with 10%Fetal Bovine Serum (FBS), 10 units/mL penicillin, 100 ug/mLstreptomycin, 2 mM glutamine, and 10 mM HEPES.

Human Reporter Cell lines—HEPM-GliLuc [MZ24]-cells (derived from HEPM,Human Embryonic Palatal Mesenchyme ATCC # CRL-1486); Growth Medium:Minimum Essential Medium (MEM; with Earle's salts) supplemented with10-20% Fetal Bovine Serium (FBS), 10 units/mL penicillin, 100 ug/mLstreptomycin, 2 mM glutamine, and 10 mM HEPES pH 7.2.

Sonic hedgehog—recombinant human SHh N-terminal octylated conjugate.

Microtiter Plates (MTPs)—For the Luciferase assay cells are plated in96-well MTPs (White, Flat-bottom, Clear-View).

Luciferase-Assay Medium—DMEM supplemented with 0.5% FBS, 10 units/mLpenicillin, 100 ug/mL streptomycin, 2 mM glutamine, and 10 mM HEPES pH7.2.

PBS/Ca/Mg Mix—Phosphate Buffered Saline (PBS) supplemented with 0.5 mMCaCl₂ and 1 mM MgCl₂.

Assay Procedure

S12 and MZ24 cells genetically modified to contain a luciferase reportergene driven by the hedgehog-responsive Gli promoter were maintained ontissue culture dishes in Growth Medium at 37° C. and 5% CO₂. Cellcultures were passaged at sub-confluency at every 3-4 days. (1:20 to1:40 for s12; 1:3 to 1:10 for MZ24). Cells were harvested and diluted inGrowth Medium such that they could be plated in a microtitre plate at10,000-20,000 cells (s12), or 20,000-30,000 cells (MZ24), per 100 ul,per well. Cells were further incubated for ˜24-48 hours at 37° C. and 5%CO₂.

After ˜24-48 hour incubation the Growth Medium in the microtitre plateswas replaced by Luciferase-Assay Medium (100 ul per well), with andwithout Sonic hedgehog-octyl conjugate, at 0.1-0.3 ug/ml (S12) or0.5-1.0 ug/ml (MZ24), and test compounds. Cells were then furtherincubated for and additional 24 hrs.

Microtitre plates were then subjected to the luciferase reporter geneassay kit (LucLite™), with modifications to the manufacturer's procedurewherein medium was removed and the substrate was reconstituted with 1:1PBS/Ca/Mg:lysis buffer instead of straight lysis buffer. In brief, thePBS/Ca/Mg was mixed 1:1 with lysis buffer and 10 mL were added to eachsubstrate vial (of the 1000-assay kit). Then the assay media from themicrotitre plate was discarded, and 100 ul of this substrate mix wasadded to each well. Plates were incubated at room temperature for 20-30minutes and then the Relative Light Units (RLUS) representing therelative expression level of the luciferase reporter gene weredetermined with a Topcount reader (Packard) or an Analyst reader(Molecular Devices). Compounds of the invention tested in the assaysdemonstrated reduced Gli expression in the reporter cell linesindicating hedgehog pathway signalling inhibition.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The preceding preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the examples, all temperatures are set forthuncorrected in degrees Celsius and, all parts and percentages are byweight, unless otherwise indicated.

The entire disclosures of all applications, patents and publications,cited herein and of corresponding U.S. Provisional Application Ser. No.60/607,367, filed Sep. 2, 2004, are incorporated by reference herein.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound of formula I:

wherein A is a carbocycle or heterocycle; X is alkylene, NR₄C(O),NR₄C(S), N(C(O)R₁)C(O), NR₄SO, NR₄SO₂, NR₄C(O)NH, NR₄C(S)NH, C(O)NR₄,C(S)NR₄, NR₄PO or NR₄PO(OH); Y is absent, CHR₄, O, S, SO, SO₂ or NR₄; R₁is selected from the group consisting of alkyl, a carbocycle or aheterocycle each of which is optionally substituted with hydroxyl,halogen, amino, carboxyl, amidino, guanidino, carbonyl, nitro, cyano,acyl, alkyl, haloalkyl, sulfonyl, sulfinyl, alkoxy, akylthio, carbamoyl,acylamino, sulfamoyl, sulfonamide, a carbocycle or a heterocycle;wherein said amino, amidino, alkyl, acyl, sulfonyl, sulfinyl, alkoxy,alkylthio, carbamoyl, acylamino, sulfamoyl, sulfonamide, carbocycle andheterocycle substituent is optionally substituted with, halogen,haloakyl, hydroxyl, carboxyl, carbonyl, or an amino, alkyl, alkoxy,acyl, sulfonyl, sulfinyl, phosphinate, carbocycle or heterocycle that isoptionally substituted with hydroxyl, carboxyl, carbonyl, amino,halogen, haloalkyl, alkyl, alkoxy, alkylthio, sulfonyl, sulfinyl, acyl,a carbocycle or a heterocycle; R₂ is halogen, hydroxyl, alkyl, acyl oralkoxy, wherein each alkyl, acyl and alkoxy is optionally substitutedwith hydroxyl, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl oralkoxy; R₃ is halogen, hydroxyl, carboxyl, alkyl, acyl, alkoxy,alkoxycarbonyl, carbamoyl, alkylsulfide, sulfinyl, sulfonyl, acarbocycle or a heterocycle wherein each alkyl, acyl, alkoxy,alkoxycarbonyl, carbamoyl, alkylsulfide, sulfinyl, sulfonyl, carbocycleand heterocycle is optionally substituted with hydroxyl, halogen, amino,nitro, alkyl, acyl, sulfonyl or alkoxy; R₄ is H or alkyl; m is 0-3; n is0-3; and salts and solvates thereof.
 2. The compound of claim 1, whereinA is a ring selected from the group consisting of A¹, A², A³, A⁴ A⁵, A⁶and A⁷:

wherein Z₁ is O, S or NR₅ wherein R₅ is H or alkyl; Z₂ is CH, CR_(2′) orN; R₂ is halogen, hydroxyl, alkyl or alkoxy; R_(2′) is H, halogen,hydroxyl, alkyl or alkoxy; and n is 0-3.
 3. The compound of claim 2,wherein A is ring A¹ wherein Z₁ is S and Z₂ is CH or N.
 4. The compoundof claim 2, wherein A is the ring A².
 5. The compound of claim 2,wherein R₂ or R₂′ is Cl.
 6. The compound of claim 1, wherein A isA^(1a), A^(1b), A^(2a), A^(3a), A^(3b), A^(4a), A^(5a), A^(6a), A^(7a)a:


7. The compound of claim 1, wherein X is NR₄C(O).
 8. The compound ofclaim 1, wherein X is NR₄SO₂.
 9. The compound of claim 7, wherein R₄ isH or Me.
 10. The compound of claim 9, wherein R₄ is H.
 11. The compoundof claim 1, wherein R₃ is Me or F.
 12. The compound of claim 1, whereinR₃ is Me and m is 1 or
 2. 13. The compound of claim 1, wherein R₃ is Fand m is 1 or
 2. 14. The compound of claim 1, wherein m is
 0. 15.-31.(canceled)
 32. A composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 33. A method of treating cancer ina mammal, comprising administering to said mammal an effective amount ofa compound of claim
 1. 34. The method of claim 33, wherein said canceris basal cell carcinoma, medullablastoma, pancreatic adenocarcinoma,small-cell lung carcinoma, breast carcinoma, rhabdomyosarcoma,oesophageal cancer, stomach cancer, biliary tract cancer.
 35. A methodof inhibiting angiogenesis in a mammal, comprising administering to saidmammal an effective amount of a compound of claim
 1. 36. A method ofinhibiting hedgehog pathway signalling in a cell comprising contactingsaid cell with an effective amount of a compound of claim
 1. 37. Aprocess for preparing a compound of formula Ib″

wherein ring B is a carbocycle or heterocycle; R₃ is halogen, hydroxyl,carboxyl, alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide,alkylsulfinyl, alkylsulfonyl, a carbocycle or a heterocycle wherein eachalkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide,alkylsulfinyl, alkylsulfonyl, carbocycle and heterocycle is optionallysubstituted with hydroxyl, halogen, amino, nitro, alkyl, acyl,alkylsulfonyl or alkoxy; R₆ in each instance is independently hydroxyl,halogen, amino, carbonyl, nitro, cyano, acyl, alkyl, sulfonyl,alkylsulfonyl, alkylsulfinyl, alkoxy, alkylcarbamoyl, alkanoylamine,alkylsulfamoyl, alkylsulfonamide, a carbocycle or a heterocycle; whereinsaid amino, alkyl, carbonyl, acyl, sulfonyl, alkylsulfonyl,alkylsulfinyl, alkoxy, alkylcarbamoyl, alkanoylamine, alkylsulfamoyl,alkylsulfonamide, carbocycle and heterocycle substituent is optionallysubstituted with amino, halogen, hydroxyl, carbonyl, or a carbocycle orheterocycle that is optionally substituted with hydroxyl, amino,halogen, haloalkyl, alkyl, alkoxy or acyl; o is 0-3; and m is 0-3; saidprocess comprising reacting a compound of formula (a)

wherein Q is Cl, Br or I; with a compound of formula (b)

wherein L is Br, I or OTf; to yield a compound of formula (c);

reducing said compound of formula (c) to give a compound of formula (d)

and reacting said compound of formula (d) with a compound of formula (e)

wherein Q′ is halogen, OH, OR wherein R is an activating group; to yieldsaid compound of formula Ib″.